Metabolism Diet

Cinderalla Solution

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Brain activity energy metabolism and neurotransmitter cycling

Epidemiological, cross-sectional and prospective associations between T2DM and moderate cognitive impairment of memory and executive functions have been discovered and were reviewed by Pasquier et al. (2006). Both vascular and non-vascular factors were found to be the reasons for dementia in diabetes (Stewart & Liolitsa 1999). Direct study using functional BOLD MRI of brain activation has shown that hypoglycaemia induced impairment of brain function is associated with task specific localised reduction in brain activation (Rosenthal et al. 2001). Higher increase of deoxygenation, depicted as higher BOLD signal in active brain areas, can help to overcome the energy shortage caused by hypoglycaemia (Rosenthal et al. 2001) or micovascular damage in type 1 diabetic patients (Wessels et al. 2006) with retinopathy. Certain overcompensation mechanisms can be observed in 31P and 1H MR spectroscopic observation of energy metabolism in type 1 diabetic patients, where, in contrast to healthy...

Homeostasis And Organ Crosstalk

The ability of the organism to sense energy status and switch between demand for energy substrates in the fasted state and their storage in the postprandial state involves close communication between the organs involved in energy homeostasis, and integration of endocrine (hormones, adipocytokines, inflammatory cytokines), metabolic (glucose, FFAs, amino acids and intermediary metabolites), and neural signals. Liver, pancreas, brain, muscle, intestine, and adipose tissue are the major organs involved in co-ordination of energy metabolism. These organs are able to communicate with each other and to sense the energy status of the entire organism, thereby coordinating their function, but the precise mechanism of this communication remains poorly understood. Two examples illustrate this point. It is still not known, for example, how the healthy pancreas senses small variations in extrapancreatic tissue insulin sensitivity in the absence of a rise in blood glucose, to modify insulin...

Patterns of weight loss in diabetes

On achieving sustainable weight loss and maintenance, it is important to recognize the above and to relay this information to the parent to allow his her better understanding of energy metabolism. Clear and frank discussion with patients in respect of difficulties in achieving and maintaining weight loss are essential. The approach to the patient by the whole healthcare delivery team as to the role of diet and lifestyle alteration needs to send the same message. It is also important that non-verbal communication to patients from the diabetic management team reinforces the verbal statements. Contradictory messages will lead to patient confusion, lack of confidence, and ultimate failure in achieving weight reduction and hence failure to achieve improved glycaemic control, blood pressure and or lipid parameters.

Dietary prevention of chronic heart failure CHF the role of micronutrients dietary fatty acids and reduced sodium intake

Finally, it has been shown that up to 50 per cent of patients suffering from CHF are malnourished to some degree,61 and CHF is often associated with weight loss. There may be multiple aetiologies to the weight loss,62 in particular lack of activity resulting in loss of muscle bulk and increased resting metabolic rate. There is also a shift towards catabolism with insulin resistance and increased catabolic relative to anabolic steroids.63 TNF, sometimes called cachectin (see above), is higher in many patients with CHF,53,63 which may explain weight loss in these patients. Interestingly, there is a positive correlation between TNF and markers of oxidative stress in the failing heart64 suggesting a link between TNF and antioxidant defences in CHF (the potential importance of TNF in CHF is discussed below in the section on dietary fatty acids and CHF). Finally, cardiac cachexia is a well-recognised complication of CHF, its prevalence increases as symptoms worsen65 and it is an independent...

The Energy Cost of Pregnancy

The energy costs of supporting a pregnancy have been estimated (5) as 20 MJ deposited as new tissue, 150 MJ deposited as fat, and 150 MJ to maintain the new tissue. However, the average increase in energy intake during pregnancy of 0.3 MJ day (1) is apparently insufficient to support this energy cost. Attempts to directly measure the energy costs of pregnancy have indicated that there is a huge interindividual variability (6). A large retrospective analysis of 360 pregnancies from ten studies incorporating a wide range of geographical and nutritional settings (6) showed that maintenance energy costs (cumulative change in basal metabolic rate) ranged from -45 to 210 MJ, energy deposition as fat ranged from -23 to 267 MJ, and total energy costs (the sum of maintenance costs, energy deposited as fat, and energy content of the conceptus) ranged from -20 to 523 MJ. Energy expenditure during pregnancy is contributed to by basal metabolic rate (BMR), thermogenesis, and maternal physical...

Avoiding Illegal Drugs

I Amphetamine (speed, Dex, crank) and ecstasy (derived from amphetamine and also called MDMA, E, X, adam, bean, and roll) increase the body's metabolic rate, resulting in hypoglycemia because the user often does not eat properly and is unaware of the onset of low blood glucose.

What Is Physical Activity

Physical activity has been defined by Caspersen et al. as 'any bodily movement produced by skeletal muscles that results in energy expenditure' (21). Components of total energy expenditure in a relatively sedentary individual include basal metabolic rate, which typically encompasses 50-70 of total energy, and the thermic effect of food, which accounts for another 7-10 (22). The remaining 20-43 is composed of energy expended through some type of 'physical activity', which can then be subdivided into energy expended in general activities of daily living (such as bathing, feeding, and grooming) and occupation, transportation, sporting and other leisure activities (see Figure 5.1).

Promotion of Weight Gain

Changes in bodyweight may be inversely related to change in HbA1c and directly related to the change in free insulin levels (Yki-Jarvinen et al 1992). Initially weight gain after a long period of poor glycaemic control may be associated with a reduction in basal metabolic rate and rehydration resulting from the amelioration of the osmotic diuresis associated with glycosuria (Makimattola, Nikkila and Yki-Jarvinen 1999). However, about two-thirds of subsequent long-term weight gain is associated with an increase in adipose tissue (Groop et al 1989), with the remaining weight gain due to an increase in lean muscle mass. Since excessive weight gain is undesirable for elderly patients with poor mobility, it is relevant that combination therapy of a single evening dose of intermediate acting insulin may be associated with less weight gain than a single morning injection, twice-daily injections and a multiple injection regimen (mean weight gain 1.2 kg, 2.2 kg, 1.8 kg, and 2.9 kg respectively...

Study of Candidate Genes

The Pima Indians of Arizona (ll9), an ethnic group with the highest reported prevalence of Type 2 diabetes and insulin resistance in the world. A point mutation in the gene encoding the beta-3 adrenergic receptor was found to be associated with an increased capacity to gain weight in a population of morbidly obese subjects (l20). The same mutation was also associated with reduced metabolic rate and early onset of diabetes (l2l), and with the development of upper body obesity and insulin resistance (l22) in two Type 2 diabetic populations.

How fast do TZDs act and how soon do they exhibit secondary failure

The onset of action of TZDs is delayed, not because of prolonged elimination half-life (3-7 hours for pioglitazone and 3-4 hours for rosiglitazone), but because of their mechanism of action that involves the activation of genes. Thus their metabolic effects are not expressed before 3-6 weeks of treatment, contrary to the other modern antidiabetic medicines. If they are administered alone, the peak action is expressed after three months, and if they are administered with a sulfonylurea or metformin, after roughly one month. In contrast with the other antidiabetic medicines that manifest secondary failure relatively quickly, several authors support the notion that the action of TZDs remains constant for at least two years.

Question can she use intrauterine contraception

The intrauterine contraceptives have little or no systemic or metabolic effects. It is an ideal, long-term method for diabetic women, especially those with vascular disease, hypertension, retinopathy, or hyperlipidemia. Most women with diabetes are excellent candidates for IUDs, and the prescription of IUDs follows the same guideline as for healthy women, that is, those at low risk for sexually transmitted infections, parous, and without recent pelvic inflammatory disease. General gynecological principles should be adhered to for proper patient selection, insertion, and monitoring in women with diabetes. None of the studies involving women with diabetes used prophylactic antibiotics with insertion or removal, and it seems unlikely that prophylaxis would add any benefit.

Effects Of Sulfonylureas On Cultured Mesangial Cells

The sulfonylureas (SULF) have long been utilized as oral agents in the treatment of type 2 diabetes mellitus (1). The primary effect of SULF is the stimulation of insulin secretion following binding to specific SULF receptors (SUR) on pancreatic 0-cells. However, SUR have extensive representation in a multitude of extrapancreatic tissues. Therefore, it is not unanticipated that SULF may induce metabolic changes aside from that of insulin secretion. These drugs have been shown to increase glucose uptake and glucose transporter (GLUT) expression in myocytes, adipocytes, and skeletal muscle cells (2-5). Moreover, we have documented significant SULF-induced metabolic effects in cultured rat mesangial cells (MCs), including alterations in mesangial matrix metabolism and MC contractility, independent of their effect on the ambient level of glycemia. The latter effect mimicked that provided by other known MC effectors of contractility, for example, atrial natriuretic peptide and angiotensin...

Question Which Intrauterine Contraceptive Should She Use The Copper Containing Intrauterine Device or the

A second medicated intrauterine contraceptive contains levonorgestrel (LVN-IUS), making it a mixed hormonal plus intrauterine system. LVN is released directly into the uterine cavity and reaches plasma levels that are 5 of the levels seen with a 105-mg dose of oral LNG. Thus, systemic metabolic effects are minimal but there is beneficial local progestin effect on the endometrium with decreased menstrual blood loss (57). A 1-year randomized trial in women with diabetes compared the LVN-IUS with the Cu-IUD and found no significant differences in fasting glucose levels, glyco-sylated hemoglobin, or daily insulin requirements at 6 weeks, 6 or 12 months postinsertion (58). The hemoglobin levels were slightly but significantly increased from baseline while the Cu-IUD resulted in a slight but significant decrease. Thus, the LVN-IUS is also a first-choice method for women with diabetes, especially those with anemia from renal disease or heavy menses.

Summary And Suggestions

Given the above considerations, the only unresolved question that remains in dietary recommendations for patients with Type 2 diabetes is what to substitute for SF. It is difficult to find any scientific justification for continuing to recommend the continued use of low SF-high CHO diets in patients with Type 2 diabetes. As discussed in this chapter, several alternative approaches are possible. Based on published data, it is suggested that replacing SF with MUFA PUFA is the simplest and most effective way to maximally improve glycaemic control, and attenuate the lipoprotein abnormalities characteristic of patients with Type 2 diabetes. In this context a diet containing (as per cent of total calories) approximately 15 protein, 45 CHO and 40 fat, with SF intake 10 of total calories, does not require a substantial change in eating habits, while effectively minimising abnormalities of CHO and lipid metabolism. However, there are alternative approaches that have as their goal the continued...

Composition Of Specialist Feeds For The Management Of Hyperglycaemia

One of the longer studies examining the metabolic effects and clinical outcomes of a modified versus a standard formula for enteral tube feeding in diabetic patients was by Craig et al. (14). This pilot study was a prospective randomised double group parallel trial in which 34 patients with diabetes were randomised to receive either modified (55 fat, 33 CHO) or standard enteral tube feeds (35 fat, 53 CHO) for up to three months. Glycaemic control was judged to be significantly better following the modified feed during weeks 1, 5 and 7. However this occurred despite any significant differences being found in the HbA1c level, fasting glucose and lipid profile

Role of Adipocyte Products and Inflammation

While circulating NEFA and several adipokines are increased in visceral obesity, the levels of the adipose-specific protein adiponectin are decreased, reducing its insulin-sensitizing effects in liver and muscle (19,30). Adiponectin signals via AMP kinase, a stress-activated signaling enzyme implicated in a variety of metabolic responses, including suppression of hepatic gluconeogenesis, glucose uptake in exercising skeletal muscle, fatty acid oxidation, and inhibition of lipolysis, which may explain its beneficial metabolic effects (30-34).

General Energetic and Molecular Consideration

The PI3K Akt mTOR pathway, HIF-1a, and Myc participate in the various facets of this metabolic phenotype. The binding of a growth factor to its surface receptor brings about activation of PI3K and the serine threonine kinases Akt and mTOR. Constitutive activation of the pathway can occur in tumors due to mutations of inhibitory regulators of these pathways, such as the tumor suppressors PTEN, TSC1, and TSC2. Metabolic effects of the PI3K Akt mTOR pathway include enhanced uptake of glucose and essential amino acids and protein translation. The transcription factor HIF-1 a is involved in determining the manner in which cells utilize glucose carbon atoms. Translation of HIF-1a is enhanced during growth factor stimulation of the PI3K Akt mTOR pathway. In the presence of oxygen, HIF-1 a is modified by prolyl hydroxylases, which target it to an ubiquitin ligase complex that includes the tumor suppressor von Hippel-Lindau (VHL) protein. This association results in a constitutive normoxic...

The Role Of The Sympathetic Nervous System

Insulin, in addition to its metabolic effects, exerts potent effects on vascular tone (51). It can also increase the sympathetic nervous system activity, which, by virtue of vasoconstriction, could reduce vascular compliance. Autonomic neuropathy may also contribute to the increased sudden death and excess cardiovascular mortality in type 1

Pentose Phosphate Pathway

AMP-activated protein kinase (AMPK) plays a major role in this exercise-related effect. AMPK is considered as a master switch in the regulation of glucose and lipid metabolism. AMPK is described as a cellular energy sensor because its activity is increased when AMP levels raise. In its activated form it affects increased catabolism and ATP generation. To accomplish this, AMPK exerts an acute regulatory role on numerous metabolic processes including fatty acid oxidation. The AMPK is an enzyme that works as a fuel gauge, being activated in conditions of high-energy phosphate depletion. AMPK is also activated robustly by skeletal muscle contraction and myocardial ischemia, and is involved in the stimulation of glucose transport and fatty acid oxidation produced by these stimuli. In liver, activation of AMPK results in enhanced fatty acid oxidation and decreased production of glucose, cholesterol, and triglycerides. The two leading diabetic drugs, namely metformin and rosiglitazone, show...

Sulfonylurea Agents Regulate Mesangial Atpsensitive K Channels

The prevailing axiom defines KATP as molecular switches that link the cell's metabolic state to calcium-dependent signaling (26). In the P-cell, SULF and or elevations of the cytosolic ATP adenosine diphosphate (ADP) ratio inhibit KATP leading to a chain of events channel closure, membrane depolarization, Ca2+ influx, and insulin secretion (25). The opposite series of events are observed with declines in the cytosolic ATP ADP ratio or after exposure to KCO. Currently, the roles of KATP are broadening with recent

Stacpoole Pw Wright Ec 1994 47-52

Hale PJ, Crase J, Nattrass M (1984) Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. British Medical Journal, 289, 1035-1038. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995) Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. New England Journal of Medicine, 333, 550-554. Taylor R, Foster B, Kyne-Grzebalski D, Vanderpump M (1994) Insulin regimes for the non-insulin dependent impact on diurnal metabolic state and quality of life. Diabetic Medicine, 11, 551557.

Diabetes Obesity and the Brain

Hypothalamus Energy Homeostasis Mc4r

The work of Rossetti and colleagues strongly supports a role for FACoA signaling in the central control of both food intake and glucose homeostasis. They found that icv infusion of oleic acid (a long-chain FFA) in rats potently reduces food intake, inhibits Npy gene expression, and increases hepatic insulin sensitivity (52) (Fig. 2). Similar responses were reported after icv infusion of an inhibitor of CPT-1 (3), the mitochon-drial transfer protein that controls the rate of fatty acid oxidation. This intervention increased hypothalamic FACoA levels and again triggered behavioral, metabolic, and hypothalamic responses that resemble the central actions of insulin and leptin. Furthermore, central CPT-1 inhibition activated neurons in brainstem areas that control parasympathetic outflow and increased hepatic insulin sensitivity through a mechanism that is blocked by vagotomy (53). Thus, hypothalamic lipid sensing is proposed to regulate hepatic glucose metabolism via the activation of...

Can Weight Loss and Exercise Improve NAFLD

The effect of exercise per se (independent of weight loss) in NAFLD has not been well studied. Most of the intervention studies in NAFLD have concentrated on the effect of weight loss alone, although a few studies have included exercise as part of the treatment program ( 349, 352-356). Studies have been small (15-65 patients), of short duration (12-16 weeks) and largely used as the primary endpoint surrogate markers (i.e., AST ALT and or ultrasound). Only Ueno et al. performed liver biopsies before and after 3 months of diet and exercise and found a reduction in steatosis (354). Moreover, none of these studies were designed to examine the effects of exercise per se from that of weight loss, but rather how both interventions were applied as part of an integrated lifestyle intervention. Recently, this issue was addressed by Tamura et al. (357) in 14 patients with T2DM exposed to a 2-week hypocaloric diet with or without moderate exercise (30-min exercise program - five to six times per...

Physiological Response To Hypoglycemia

Epinephrine sharply increases EGP during hypoglycemia. Secreted by the adrenal medullae, epinephrine binds to multiple receptors and causes an array of hemodynamic and metabolic effects. Through its actions (direct and indirect) on diverse target tissues, the hormone stimulates both glucose production and the limitation of glucose utilization by mainly beta adrenergic receptors in humans (1-3,7-9).

Physical activity and obesity

Exercise is the most variable component of energy expenditure it is therefore clear to see why exercise has been adopted as a component to treat overweight and obesity. Indeed, exercise or physical activity is promoted within a range of guidelines for the prevention and treatment of overweight and obesity (WHO, 1997 NIH, 1998). Understanding the impact of physical activity and exercise on obesity and associated variables is important, as an increase in physical activity not only has significant positive effects on body mass and body fat mass, but also on a range of other variables associated with health (Blair and Brodney, 1999). Physical activity has been suggested to have favourable effects on weight loss, decreased fat percentage, decreased skinfold thickness, android disease, decreased risk of coronary heart disease (CHD), improved glucose metabolism, increased basal metabolic rate (BMR), prevention of loss of fat free mass (FFM), increased dietary thermogenesis, reduced blood...

Mechanism Of Action

Glucose Mechanism Action

The thiazolidinediones are highly selective and potent agonists for the PPAR-g (Fig. 1) (5,6). These receptors are important regulators of adipocyte differentiation, lipid homeostasis, insulin action, and vascular endothelial function and are found not only in key target tissues for insulin action, such as adipose tissue, skeletal muscle, and liver, but also in the vascular endothelium, macrophages and other cell types (5,6). The thiazolidinediones act, at least in part, by binding with PPAR-g in various tissues to influence alter the expression of a number of genes encoding proteins involved in glucose and lipid metabolism, endothelial function and atherogenesis (5-7). The glucose-lowering effects of the thiazolidinediones involve the alteration of the expression of several genes involved in glucose and lipid metabolism, including glucose transporter (GLUT)1, GLUT4, leptin, tumor necrosis factor-a, hepatic glucokinase, Phosphoenolpyruvate carboxykinase (PEPCK), fatty acid (FA)...

Dilys J Freeman and Naveed Sattar

Energy Metabolism in Pregnancy Maternal adaptations in energy metabolism are required to respond to the additional energy demands of pregnancy, and these adaptations are influenced by the degree of maternal obesity. Glucose intolerance does not influence the adaptation of maternal energy metabolism to pregnancy. Pregnancy is associated with increased maternal insulin resistance, which is further increased in obese and glucose-intolerant mothers. Endothelial function is improved in pregnancy but to a lesser extent in obese and glucose-intolerant mothers. While these changes in maternal metabolism and physiology in response to pregnancy have been described, the timing and the resulting impact on the quality of circulating maternal metabolites are poorly understood. An appreciation of the detail of these processes is important in order to inform our understanding of how obesity and glucose intolerance may contribute to adverse pregnancy outcome and to allow the development of sensible,...

Metabolic Changes During Pregnancy

Fundamental changes occur in maternal metabolism and physiology during pregnancy. Over 280 days the mother's weight increases on average by 12.5 kg. The main increase in weight occurs in the second half of pregnancy and is caused by the growth of the conceptus, the enlargement of maternal organs, maternal storage of fat and protein and an increase in maternal blood volume and interstitial fluid. An increase in the basal metabolic rate results in the need for increased energy intake. In addition throughout pregnancy maternal metabolism

The Metabolic Syndrome in PCOS

Obesity tends to be abdominal in its distribution in PCOS women, and even lean-affected women may have a fat distribution favoring visceral depots, particularly in the abdomen (81). This is not unexpected, since androgens do in fact have an important role in the regulation of fat metabolism, differentiation, and morphology, through specific receptors whose distribution and characteristics vary according to different fat localization (101). Importantly, stimulation with androgens seems to upregulate the expression of their own receptors (102), but estrogens downregulate the density of these receptors (103). For more details on the effect of androgens on body fat distribution patterns, please see Section Androgens in Chap. 1. Interestingly, testosterone in physiological concentrations appears to inhibit catecholamine-induced lipolysis in differentiated preadipocytes from the subcutaneous

Peroxisome Proliferatoractivated Receptor Ppary Agonists And Treatment Of Alzheimers Disease

PPAR-y is also involved in the regulation of energy metabolism via increased glucose metabolism and direct effects on mitochondria (96) that possibly increase astrocytic lactate production and glucose consumption (97). Additionally, PPAR-y agonists may promote cell health through anti-inflammatory actions directed toward mitochondria. These agonists initiate a protective cascade that increases k(kappa)B expression and blocks NFK(kappa)B expression thereby reducing inflammatory gene expression and inflammatory responses. Therefore, PPAR-y is a novel therapeutic target for Alzheimer's disease that may reflect diverse affects, including improving energy metabolism, improving glucose uptake, and mounting an anti-inflammatory response. Rosiglitazone may offer a promising novel therapeutic strategy for the treatment of Alzheimer's disease. Several different mechanisms may account for its actions, the most prominent of which is its ability to improve insulin sensitivity. Other mechanisms...

Insulin Resistance and Its Relevance to Treatment

Catecholamines And Insulin Resistance

Insulin exerts its metabolic effects on the insulin-sensitive tissues, i.e. on liver, muscle and adipose tissue. In these tissues, insulin action is the result of complex mechanisms. We can distinguish (1) insulin binding to specific receptors and the following sequence of events along the insulin signalling pathway, which ultimately lead to (2) the insulin metabolic effects at postreceptor level. Metabolic Effects of Insulin (Postreceptor Effects) Table l. Metabolic effects of insulin Table l. Metabolic effects of insulin

Hormonal Contraception

Hormonal contraception contains either a progestin compound alone or in conjunction with estrogen. They can be administered orally, intramuscularly, transdermally, and transvaginally. Some IUDs also contain progestin. Estrogen does not affect glucose tolerance (5), but progestins do increase insulin resistance and decrease glucose tolerance in a dose and potency fashion (6-8). Estrogen slightly increases blood pressure (9) by increasing angiotensin production while progestins have no effect. Estrogens produce an increase in clotting factors while progestins have no effect (10-14). Estrogens favorably affect lipid profiles, decreasing LDL-cholesterol and increasing HDL-cholesterol, while progestins produce an opposite effect (15-19). Estrogen increases triglycerides, while progestins have no effect. When estrogens and progestins are combined as in combination oral contraceptives (COC), the lower doses and less androgenic progestins generally produce milder and a more estrogen-dominant...

Structural Abnormalities In Type And Type

Diabetic Neuropathy Myelinated Axon

One of the earliest detectable structural changes in sensory myelinated fibers is the conspicuous enlargement or swelling of the nodal and paranodal axon, which correlates with the early Na+ K+-ATPase defect and increased axonal Na+J (30,33) and is reversible after metabolic corrections. This abnormality is less frequent in early type 2 DPN in the BBZDR Wor-rat, probably related to the milder defect in the Na+ K+-ATPase activity (31,56). Other early ultrastructural abnormalities observed in sensory nerves consist of glycogen accumulation in axonal mitochondria, so called glycogeno-somes, and misalignment of neuroskeletal structures (74,75). These structural changes are likely to reflect impaired axonal energy metabolism (74,76) and aberrant phosphorylation and nonalignment of particularly neurofilaments, respectively (75,77-79). Maligned neuroskeletal elements appear to induce phagocytotic activities by the Schwann cell that extends cytoplasmic loops engulfing abnormal axoplasm...

The Coagulation System And Diabetes Mellitus

Decreased activity of antithrombotic factors in blood can potentiate thrombosis. Of note, concentrations in blood of protein C and activity of antithrombin are decreased in diabetic subjects. Unlike changes in concentrations of prothrom-botic factors, altered concentrations and activity of antithrombotic factors appear to be reflections of the metabolic state typical of diabetes such as hyperglycemia, regardless of whether type 1 or type 2 diabetes is responsible. In fact, decreased antithrombotic activity has been associated with nonenzymatic glycation of anti-thrombin.

Obesity and inflammation

Resistin, discovered as a gene suppressed by rosiglitazone in mouse adipose tissue, earned its name because it induced insulin resistance.53 Thiazolidenediones (TZDs) suppress resistin concentrations in humans while inducing an increase in adiponectin concentration consistent with the anti-inflammatory effects of these drugs. Furthermore, it has been shown that the increase in adiponectin and the decrease in resistin occur early after rosiglitazone treatment along with manifestations of other anti-inflammatory effects prior to any changes in plasma concentrations of insulin, glucose, or FFAs. Thus, these early anti-inflammatory effects are independent of the metabolic effects of TZDs.54

Corsi Minerva Kolesar

Allie EC, Kane MP, Busch RS, Bakst G, Hamilton RA. Orlistat in Obese Patients with Type 2 Diabetes A Retrospective Assessment of Weight Loss and Metabolic Effects. Hospital Pharmacy 2004 39(1) Versari G, Cuttica CM, Falivene MR, Devoto GL, Boletto N, Ferrari B, Corsi L. Orlistat in obese type 2 diabetes mellitus metabolic effects of a short term treatment. Journal ofEndocrinological Investigation 2000 Suppl 46.

How Obesity Causes Diabetes Not a Tall Tale

During starvation, it is the fall in circulating leptin levels that triggers increased appetite and decreased metabolic rate. Consistent with this, rodents and humans with only one functional copy of the leptin gene have increased body fat (14), and leptin deficiency due to lipodystrophy causes insulin resistance (15, 16). Because a reduction in leptin levels appears to be the physiological signal for a thrifty metabolic response, leptin itself must have been evolutionarily selected for another function. Indeed, leptin replacement reverses amenorrhea in leptin-deficient females with low body weight (17), providing the mechanistic explanation for the link between body fat and reproductive capacity that was first proposed three decades ago by Frisch on the basis of epidemiological studies of indigenous and modern populations (18). This physiological function of leptin thus favors survival of the species by conferring a reproductive advantage to individuals who are...

Neuroendocrine Findings Associated With Depression

The hypothalamic-pituitary-adrenal (HPA) axis mediates the ability of an organism to respond to threats, including stress. Interestingly, the determining characteristics of stressors which provoke depression in humans (namely entrapment, humiliation, and loss) provoke animal models of depression. Following exposure to a stressor, the hypothalamus releases corticotrophin-releasing hormone (CRH) which in turn stimulates the release of adrenocorticotrophic hormone (ACTH) by the anterior pituitary gland. This causes the adrenal glands to release glucocorticoids, including cortisol. Glucocorticoids interact with receptors in most body tissues, particularly in the regulation of energy metabolism. Glucocorticoids eventually bind corticosteroid receptors in the hippocampus which then act to inhibit further production of CRH and ACTH, shutting down the loop. This fast feedback operates over the course of minutes. This system allows the flight or fight response, in which pulse and blood...

Mechanisms responsible for the overexpression of pai in diabetes

Increased expression of PAI-1 in diabetes is undoubtedly multifactorial. A direct effect of insulin on the expression of PAI-1 has been suggested by a positive correlation between the concentration of insulin and PAI-1 in vivo (93,94,96,100-103,106). Triglycerides and their constituents (fatty acids) appear to contribute to the overexpression of PAI-1 in view of the fact that both insulin and triglycerides independently increase expression of PAI-1 by human hepatoma cells in vitro (105,107-109). Liver steatosis is another determinant of elevated concentrations of PAI-1, perhaps indicative of the response of both to derangements in the tumor necrosis factor signaling pathway (110). Insulin and triglycerides exert a synergistic increase in accumulation of PAI-1 in conditioned media when both are present in pathophysiological concentrations (105). Analogous results are obtained with insulin in combination with very low-density lipoprotein-triglyceride, emulsified triglycerides, or...

The Energy Cost of Pregnancy in Gestational Diabetes Mellitus

In common with others, Okereke et al. (11) observed an increase in BMR from the prepregnant state to late pregnancy in obese women with normal glucose tolerance (NGT) and obese women with gestational diabetes mellitus (GDM). There were no significant differences in basal energy expenditure between NGT and GDM obese women (11). Obese GDM women had total energy expenditure similar to that of obese NGT women (11). Similar observations were made for lean GDM and NGT women (18). GDM women had oxygen consumption, CO2 production, total energy expenditure, and BMR similar to that of controls after correction for higher body mass (19). It is, therefore, suggested that the adaptations of energy metabolism to pregnancy are not influenced by glucose intolerance. This is possibly due to the placental production of hormones overriding any localized influence of maternal metabolic abnormalities (11).

The Glucose Sensing System A Basic Model

How Model Diabetes Type

The basic model of glucose-stimulated insulin secretion may thus be summarized as follows. An increase in circulating glucose concentration is sensed by the P-cell via a proportional increase in metabolic rate. Both glucose transport and glucokinase participate in this translation of glucose concentration into insulin secretion via the regulation of the entry of glucose into glycolysis, with a dominant role being played by glucokinase, as discussed. The activation of glycolysis increases the phosphate potential (ATP ADP + Pi) by the generation of ATP at three sites (1) the distal portion of glycolysis, (2) shuttling of reducing equivalents into the mitochondria and activation of the electron-transport chain and oxidative phosphorylation, and (3) pyruvate oxidation. The increase in ATP (ADP + Pi) causes inhibition of KATP channels, because ATP4- is an inhibitor and MgADP- is an activator, resulting in membrane depolarization and Ca2+ influx. The rise in intracellular Ca2+ triggers...

Individual drug review

A few unfavorable metabolic effects of bBs were reported. bBs might exacerbate glucose intolerance 5,45,46 , increase triglycerides, and decrease high-density lipoproteins 47 . These effects on surrogate end points should not prevent us from using bBs in diabetic patients who have hypertension. Caution should be taken when using bBs in diabetic patients who are at risk for severe hypoglycemia, although there is no convincing evidence that b1-selective blockers increase the risk of masking hypoglycemia symptoms 48-50 . High dosages of selective b1-block-ers should be avoided in patients who have asthma or severe obstructive lung diseases. bBs should not be used in patients who have advanced heart block or sinus node disease without a pacemaker.

Mechanisms Adipoinsular Axis

The mechanisms behind the metabolic effects of a diabetic intrauterine environment on exposed offspring are not entirely understood. In 1980, Freinkel's Banting Lecture focused on the hypothesis of fuel-mediated teratogenesis (7), which suggests that permanent changes in fetal development occur as a result of exposure to altered maternal fuels in the mother with diabetes. Fetal growth is deranged in pregnancies complicated by diabetes (57), and the excess growth appears to be mainly driven by increased adipose tissue (16). The adipoinsular axis is a proposed endocrine feedback loop that connects the endocrine pancreas with the adipose tissue and the brain to regulate hunger and fat storage through the hormones, insulin and leptin. Insulin promotes fat mass and leptin production, while leptin acts to reduce energy intake and also suppresses insulin secretion via leptin receptors on pancreatic b cells. Abnormal functioning of this feedback loop may, therefore, lead to excess adiposity,...

Role For Vascular Vs Nonvascular Mechanisms

Transduction and metabolic effects that could be completely independent of vasodilator properties of these agents. Lisinopril acts as a weak antioxidant (30) and nitric oxide scavenger (31). The spectrum of pharmacological effects of salbutamol is even more impressive the agent inhibits expression of intercellular adhesion molecule-1, CD-40, and CD-14 (32) as well as eicosanoid biosynthesis (33), increases intracellular cyclic adenosine monophosphate concentration, cyclic adenosine monophosphate-dependent PKA, adenylyl cyclase, phosphatase PP2A and L-type Ca2+ channel activities, modulates G protein signaling (34), and stimulates pentose phosphate pathway (35). At least, several of these effects might account for better MNCV response to ISO plus salbutamol in comparison with ISO plus lisinopril treatment.

Actions of Insulin and Glucagon

Although insulin and glucagon may be considered as the primary hormones responsible for the development of DKA, increased levels of the stress hormones epinephrine, norepinephrine, cortisol, and growth hormone play critical auxiliary roles. Epinephrine and norepinephrine activate glycogenolysis, gluconeogenesis, and lipoly-sis and inhibit insulin release by the pancreas. Cortisol elevates blood glucose concentration by decreasing glucose utilization in muscle and by stimulating gluconeogenesis. Growth hormone increases lipolysis and impairs insulin's action on muscle. The cata-bolic and metabolic effects of each of these counterregulatory hormones are accentuated during insulin deficiency (2,3,6). Under experimental conditions, the hyperglycemic effect of all of these counterregulatory hormones infused together is greater than the sum of the effects of the individual hormones that is, the effects are synergistic and not merely additive. Even in normal persons, high concentrations of...

Treatment for Diabetes Mellitus A Potential Therapy for Breast Cancer

Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Some of the beneficial effects of metformin have been linked to activation of AMPK in muscle, adipose tissue, and liver. AMPK is a protein kinase which regulates energy metabolism and is activated by an increase in the intracellular ratio of AMP ATP. Upon activation, AMPK phosphorylates a number of effector proteins leading to the activation of ATP-generating pathways, such as glycolysis, and the inhibition of ATP-consuming pathways. Activation of AMPK inhibits cancer cell proliferation through various mechanisms, including TSC2-dependent inhibition of mTOR and phosphorylation of p53. Treatment of breast cancer cells with metformin has been shown to inhibit their growth through the activation of AMPK 52 . In C3H Sn mice, which are susceptible to breast cancer, long-term administration of phenformin reduced the incidence of mammary carcinoma from 80 to 21 53 . In humans, a case-control...

Cognitive restructuring

Emotional factors may have considerable impact on a person's dedication to weight change and may be a strong antecedent to overeating or abandoning activity. Negative affect and self-defeating cognitions regarding one's ability to succeed in making behavioural changes may hamper future efforts. Most obese persons have endured many unsuccessful weight loss attempts and this history can fuel maladaptive expectations of future failure if not addressed as a part of comprehensive behavioural treatment. Negative self-attributions associated with failure to lose weight (e.g. 'can't do it', 'weak', or 'don't have the willpower'), or inaccurate physical attributions such as having a resistant or 'slow metabolism' are frequently encountered in weight treatment. While the latter may seem desirable as a potential explanation for failure to achieve weight loss despite repeated efforts, one recent study rejected this phenomenon as a primary explanation for failure to lose weight (Lichtman et al.,...

Experimental Illustrations Of The Basic Model

Secretory and metabolic responses of isolated pancreatic islets. Panels A and B show insulin, glucagon release and O2 consumption upon stimulation with glucose and amino acids. Cultured rat islets (4-5 d at 10 mM glucose) were layered between cytodex beads, resulting in a 1 X 2-cm columnar arrangement allowing perifusion at a rate of approx 2 mL min. Clark oxygen electrodes were used to measure the arteriovenous (AV) difference of O2 to calculate the respiratory rate. Samples from outflow were collected every 2 min to measure insulin and glucagon content. The conditions were changed as indicated in the panels. Fig. 2. Secretory and metabolic responses of isolated pancreatic islets. Panels A and B show insulin, glucagon release and O2 consumption upon stimulation with glucose and amino acids. Cultured rat islets (4-5 d at 10 mM glucose) were layered between cytodex beads, resulting in a 1 X 2-cm columnar arrangement allowing perifusion at a rate of approx 2 mL min. Clark oxygen...

Classification of Diabetes Mellitus

Type 2 diabetes is a more heterogeneous disease compared to type 1 diabetes. Most subjects with type 2 diabetes have a condition called insulin resistance. This is a state in which more than normal amounts of insulin are needed to produce a normal metabolic response to insulin.22 Insulin resistance is asymptomatic and may be found in subjects years before they develop type 2 diabetes.2324 As long as the pancreas is able to secrete increased amounts of insulin to counter the reduced response to insulin, blood glucose levels stay within the normal range in individuals with insulin resistance. If the pancreas is unable to keep up with the demand for higher insulin secretion rates, blood glucose concentrations start to rise and diabetes may ensue. Biochemical investigation has shown that insulin concentrations are higher than normal in subjects with insulin resistance and are normal in patients with type 2 diabetes of short duration.25 Thus, patients with type 2 diabetes have relative...

Program for Early Diabetics

The total fiber content is between 25 and 50 grams daily. The HCF diet produces many positive metabolic effects, including the following lowered post meal hyperglycemia and delayed hypoglycemia increased tissue sensitivity to insulin reduced low-density lipoprotein (LDL) cholesterol and triglyceride levels and increased high-density lipoprotein (HDL) cholesterol levels and progressive weight loss. Dr. Anderson provided me some valuable information Yet, I found I could optimize my diet even better and get better results.

Role Fatty Acids in the Control of Insulin Secretion

Transporters and is rapidly phosphorylated to glucose-6-phosphate (G-6-P) by glucokinase that acts as the glucose sensor or pacemaker for insulin secretion (379). Glucokinase is the rate-limiting step for insulin secretion as the capacity of GLUT2 to transport glucose inside the P-cell is much greater than the capacity of glucokinase to phosphorylate it. Most of the glucose is then converted through glycolysis to pyruvate (P-cells have limited capacity to generate glycogen or lactic acid from glucose), entering the mitochondria and generating ATP through the Krebs cycle as acetyl-CoA. This promotes the formation of citrate, which is transported to the cytoplasm inhibiting CPT-1, which is the transporter of fatty acids (as long-chain fatty acyl-CoA) into the mitochondria. This way, malonylCoA acts as the metabolic switch for insulin secretion from the fasting to the fed state FFA goes from being oxidized as a fuel for basal insulin secretion in the fasting state, to being stored within...

Precipitating Factors

The cardinal feature of DKA is a deficiency of insulin action brought about by an absolute or relative lack of insulin (1,7,16). In newly diagnosed patients or when insulin therapy has been omitted, an absolute lack of insulin is responsible for the development of DKA (7,16). In contrast, during acute illness, stress, most commonly the result of an infection, causes DKA to result from a relative deficiency of insulin, with insulin's action opposed by the surge in the counterregulatory hormones, glucagon, catecholamines, cortisol, and growth hormone (1-4). Acute and severe emotional stress may be an important precipitating factor for DKA in children (6,11). In most instances, emotional factors such as parental discord, peer pressure at school, and adolescent adjustment problems may serve to worsen an already disturbed metabolic state (6,7). In rare instances, these factors may appear to be the sole precipitating cause for DKA. However, the most common precipitating change in patients...

Variations In Glycaemic Index

Perhaps the best example of the ability of differences in glycaemic index of CHO-enriched diets to modify glycaemic control and lipoprotein metabolism in patients with Type 2 diabetes is the report by Jarvi and colleagues (38). These investigators compared the metabolic effects of two diets, each containing 55 of total calories as CHO, in 20 patients, consuming each of the test diets for 24 days. The glycaemic indices were calculated to vary from 57 to 83 as compared to white wheat bread. The two test diets were compared to each other, as well as to baseline values obtained on an uncontrolled diet. Of considerable interest was the observation that fasting plasma glucose, TG, and LDL cholesterol concentrations fell on both diets, supporting the general belief that essentially any prescribed diet is better than no diet plan. On the other hand, the degree of improvement in all of these variables was the same, irrespective of the difference in glycaemic index of the diet. Furthermore, the...

Energy Requirements In Pregnancy

Pregnancy is an anabolic state requiring energy for the products of conception, the foetal-placental unit and the increase in maternal tissues. Newly synthesised maternal tissues account for a 15-26 increase in metabolic rate in pregnancy (26). The total calculated energy cost for pregnancy is around 355 640 kJ (85 000 kcal) and this translates into an extra 1191.3 kJ (285kcal) a day (27,28). These theoretical energy costs, originally derived in the 1960s by Hytten and Leitch, have been confirmed by more recent physiological measurements (29).

The Impact of Maternal Obesity on the Energy Cost of Pregnancy

The total energy cost of pregnancy is positively associated with prepregnancy fat mass, body fat, and pregnancy weight gain (6), but maintenance costs are only associated with prepregnancy fatness. This might be explained by the fact that prepregnancy fatness is a marker of overall nutritional status or that prepregnancy fatness may indicate a positive energy balance before conception, and this energy balance might be maintained throughout pregnancy. Either mechanism would explain the wide variability in metabolic response to pregnancy and serve to match energy requirements to energy availability, hence optimizing fetal growth. Leptin has been suggested to be the signal that may link prepregnancy fatness with the maternal metabolic response to pregnancy (5). Butte et al. (13) compared energy metabolism in women with a low, normal, and high body mass index (BMI). The increase in BMR during pregnancy was highest in a high BMI ( 26 kg m2) group at 16.3 (5.4) kcal week compared with a...

The Biology Of Sex Difference In Health And Disease

There is increasing evidence that there are many differences between the sexes in the susceptibility and development of chronic metabolic diseases and cardiovascular diseases (CvDs). This implies that mechanisms may partly differ in males and females, involving both endogenous and environmental factors. The fundamental differences between males and females are primarily attributed to hormones, which define the differentiation of secondary sex characteristics at puberty, regulate fertility, metabolism, and behavior, as well as play an important role in regulating many functions of nonreproductive tissues (1). Androgens are fundamental examples of this sex-related hormonal function. They have different functions with typical genomic influences on protein synthesis mediated by transcription induced as a result of the binding of hormones to intracellular receptors and DNA, and by means of these actions they regulate body composition and fat metabolism as well as vascular function and...

Population lessons from the pcos paradigm

Women present the opposite relationships between endogenous androgens and obesity, insulin, DM2, and cardiovascular risk factors (40). As reported above, abdominal obesity in women is a relative hyperandrogenic state, due to increased androgen production rates not adequately compensated by a parallel increase of their metabolic rates. This relative excess of free androgens is also due to the decrease of SHBG concentrations, that generally occurs in abdominally obese women as well as in other conditions of moderate-to-severe insulin resistance (2). Notably, decreased SHBG levels are an independent risk factor for the development of DM2 (144).

Lipid Metabolism In Pregnancy

There is no change in either basal carbohydrate oxidation or nonoxidizable carbohydrate metabolism but there is a significant 50-80 increase in fat oxidation during pregnancy both in the basal state and also during an euglycemic hyperinsulinemic clamp (11). These data underline the importance of the switch from carbohydrate to fat metabolism in pregnancy that is potentially regulated by placenta-produced leptin. During fasting, pregnancy is a state of accelerated starvation with increased maternal reliance on lipids rather than on carbohydrate for energy demands (62). These maternal responses to pregnancy have the result of sparing carbohydrates and amino acids for the fetus. Decreased PPARg expression, and hence signaling through its target genes, has been suggested to be the mechanism by which fat catabolism is enabled (63).

Diabetes And CardiovASCuLar Risk Factors In Women

Obesity is one of the most important risk factors for DM2. In North America as well as in Europe and East Asia, the number of people considered overweight or obese is dramatically increasing (61), involving approximately half the population. Sex differences in weight are clearly influenced by geography and ethnic background. For example, data coming from the United States show that among whites and Mexican Americans, the prevalence is higher among men than among women. However, among black Americans, the prevalence of being overweight or obese is higher in women than in men (62). These figures are more or less similar in Canada (63). In Europe these trends are also similar, although the extent of this epidemic appears to be lower (61). In addition, obesity is also prevalent in many developing countries, with some geographical and ethnic differences. Collectively, prevalence rates appear to be similar for the two sexes, although available data suggest that countries reporting higher...

The Insulin Receptor Transduction through Tyrosine Kinase

An understanding of insulin resistance requires knowledge of the mechanisms of insulin action in target tissues, such as liver, muscle and adipose tissue. The net responses to this hormone include short-term metabolic effects, such as a rapid increase in the uptake of glucose, and longer-term effects on cellular differentiation and growth 12 . The a-subunits of the insulin receptor are located extracellularly and are the insulin-binding sites. Ligand binding promotes autophosphorylation of multiple tyrosine residues located in the cytoplasmic portions of p-subunits. This autophosphorylation facilitates binding of cytosolic substrate proteins, such as IRS-1. When phosphorylated, this substrate acts as a docking protein for proteins mediating insulin action. Although the insulin receptor becomes autophosphorylated on tyrosines and phosphorylates tyrosines of IRS-1, other mediators are phosphorylated predominantly on serine and threonine residues. An insulin second messenger, possibly a...

Adipose Tissue as an Endocrine Organ

The link between abnormal fat cells and inflammation. Adipocytes develop from preadipocytes present in adipose tissue and their main mission has classically been restricted to the regulation of triglyceride storage and overall body energy metabolism by the secretion of hormones such as leptin. The observation by Hotaqmisligil et al. (123) and Feinstein et al. (124) that the fat-derived proinflammatory cytokine TNF-a could induce insulin resistance was a radical departure from the classical view of adipose tissue. While the role of TNF-a to induce insulin resistance in humans with T2DM remains controversial, nevertheless the realization that adipocytes were actively involved in the secretion of many inflammatory cytokines previously believed to be secreted only by macrophages - or simply unknown - opened a new horizon in the understanding of insulin resistance, obesity and T2DM i.e., TNF-a. IL-6, resistin, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibi-tor-1...

The Diabetic Surgical Population

It is estimated that 6.0 million patients develop significant hyperglycemia each year while in the hospital. Many of these patients will have a prior diagnosis of type 1, type 2, gestational, or secondary diabetes. Approximately half of the hyperglycemic patients will have previously undiagnosed diabetes and will require insulin or oral hypoglycemic therapy following discharge from the hospital (27-29). A significant number of non-diabetic patients will develop hyperglycemia due to the metabolic effects of anesthesia, tissue trauma, pain, systemic illness, and infection (1-3). Although insulin is often required during the stressful event, medication is often not required following hospital discharge. The number of surgical patients with diabetes and impaired glucose tolerance (IGT) is expected to increase over the next 15 years, due to the aging baby-boom population, the sedentary lifestyle of the US population, and the increasing incidence of obesity (26,29).

Nutritional Considerations

Quently thought to be hypometabolic and are often treated with thyroid or other hormones to facilitate weight loss. This is neither safe nor necessary moreover, the observed minus the total predicted energy expenditure varies in relation to weight progression (368). Patients who gain weight increase their metabolic rate whereas those who are on diets and are losing weight may reduce their energy expenditure by 10 to 20 . Thus the results of dietary efforts can only be successful if the reduced intakes are accompanied by increased energy expenditures to overcome the metabolic adaptations that occur with dieting.

Pathophysiology of glycaemic vascular injury

The abnormal metabolic state associated with type 2 diabetes is associated with chronic low-grade inflammation, endothelial dysfunction, dyslipidaemia and insulin resistance (see also Chapter 2). These factors confer an increased risk of atherosclerosis and PAD, and have led to new hypotheses about the pathogenesis of macrovascular complications and the interactions between metabolic, endocrine and haemodynamic mechanisms. Four pathways have been proposed to explain how hyperglycaemia specifically affects vascular structure and function in the lower limbs

Combination Therapy Is Mandatory For Most Patients To Reach Target Values

As clearly stated by recent guidelines (80,81) most patients with diabetes will require two or more antihypertensive therapies from different classes with complementary mechanisms of action to control their blood pressure. Thiazide diuretics, BB, or CCB can be added to ACEi or ARB treatment to achieve target BP, either as an individual drug component or as part of a fixed-dose combination product. Combining an ACEi or an ARB with a thiazide diuretic may be particularly effective, as such combinations provide additive reductions in blood pressure compared with individual monotherapies, and counteract many of the adverse events that may be associated with the use of high doses of thiazide diuretics (82,83), and abolish any interracial differences in the response to ACEi or ARB monotherapy (84,85). For example, coadministration of irbesartan and hydrochlorothiazide, either as individual components or in a fixed dose combination, leads to additive reductions in blood pressure in a diverse...

Practicalities Of Feeding Hospitalised Patients

Although the metabolic consequences of diabetes are known to involve fat metabolism resulting in a significant dyslipidaemia, there are few defined management targets for serum lipids when giving nutritional support to diabetic patients. The degree of dyslipidaemia is frequently disproportional to

Variations In Fibre Content

When put into the context of results of earlier studies evaluating variations in fibre content, it appears that the clinical benefit is closely related to the increment in daily fibre intake. More specifically, increases in fibre intake of * 15 g day did not lead to any significant metabolic changes (44,45), whereas dietary increases up to 23 g day (46) and 30 g day (47) resulted in a modest improvement in glycaemic control, without any decrease in plasma TG concentration. Thus, there appears to be no study in which the untoward metabolic effects of CHO-enriched diets have been shown to be attenuated to the degree seen when MUFA PUFA fat is used to replace SF (20), and the only instance in which the effects were even comparable involved the daily intake of 50 g fibre (43).

Sex Differences In Energy Balance

One of the major determinants of basal or resting metabolic rate and total energy expenditure is body composition, more specifically fat-free mass (8). Thus, because of higher fat-free mass, men generally have higher energy expenditure measurements on an absolute basis than women. Analyses where body composition differences were controlled for indicate, however, that resting and 24-h energy expenditure may be higher in men than in women, independent of body composition (9). This difference is relatively small, but can be detected in elderly individuals as well as prepubescent boys and girls, suggesting that it is independent of hormonal status (10).

Changes in Body Composition Associated with Pregnancy

Baseline energy intake and change in energy intake during pregnancy were not correlated with the gestational fat gain during pregnancy. Prepregnancy weight, fat mass, and fat-free mass also did not predict the amount of fat deposited. There was some evidence that women with higher resting metabolic rates prepregnancy gained more fat (5, 23).

Why was a thiazolidinedione TZD added to the regimen of this particular patient

Since there was an improvement of the metabolic control with the addition of the TZD but not yet complete achievement of the targets, and since the medicine was well tolerated, it was decided to give the patient more time to allow the full effect of the medicine. It is reminded that sometimes many months are needed (up to 8-9) for the full manifestation of the metabolic effects of TZDs.

Placebocontrolled trials of diureticbased and betablockerbased therapy

Despite the fact that raised blood pressure is frequent among individuals with diabetes 4,5 , many of the earliest randomised trials either excluded diabetic patients or failed to report their inclusion. This may have been due to concerns about possible adverse metabolic effects of diuretics and beta-blockers 17 or concern that diuretics might increase mortality among hypertensive subjects with diabetes 9,10 . The INDANA Collaborative Group conducted a metaanalysis of individual participant data from three trials (HDFP, STOP-Hypertension and SHEP 18-20 ) that did include diabetic participants, that used mainly diuretics as first-line therapy (with some use of beta-blockers), and that collected data on fatal and non-fatal stroke 21 . In combination, among 2,162 diabetic participants with hypertension, active treatment lowered blood pressure by 11 4mmHg more than placebo. The relative risk of stroke was reduced by 36 (95 CI 10-55) (Figure 2), a result virtually identical to that...

Physiology Of Exercise

In people without diabetes, a precise endocrine response ensures that the energy needs of the exercising muscle are met and glucose homeostasis is maintained. This metabolic response is ameliorated in Type 2 diabetes and lost in Type 1 diabetes and the challenge is to reproduce the physiological state of the non-diabetic individual. A brief review of the metabolic, hormonal and physiological responses to exercise is given below. Metabolic changes provide the energy required for exercise. Glucose uptake by exercising muscle increases and at the onset of exercise, muscle glycogen is converted to lactate to provide the energy substrate. When muscle glycogen is exhausted, energy is provided by glucose from the liver following glycogen-olysis and eventually from metabolism of free fatty acids in adipose tissue. The metabolic response depends on a number of factors People with Type 2 diabetes usually have sufficient circulating insulin to precipitate the normal metabolic response to...

What About a Weight Loss Pill

Imagine how much easier it would be if instead of following a diet you could just take a pill every day that would reduce your appetite, increase your metabolism, and not put you at any risk. That isn't a complete daydream. In the past decade there has been an explosion in the scientific understanding of the molecules in our body that control appetite and metabolism. This new research may someday lead to the creation of a magic pill for weight loss. But it hasn't happened yet, and past experience is sobering. There are of course dozens of nonprescription pills, sold as diet supplements, that do not fall under the watchful eye of the FDA. The pills and nostrums promise to help weight loss by stimulating your nervous system, targeting fat stores for digestion, resetting a disordered cortisol system, balancing your metabolism, and performing a variety of other unproven actions. None of these miracle cures, advertised in tabloids, have ever been shown to work in rigorous studies. Save...

Physical Activity And Fitness

The television programs may be more important than the number of viewing hours. However, it has been recently shown that television viewing has a fairly profound lowering effect on metabolic rate in both lean and obese individuals. Also, a TV in the child's bedroom is an even stronger marker of increased risk of being overweight especially in preschool children (390). This may be an important factor in susceptible children who are at risk for weight gain and potentially lead to obesity (385).

Human Single Gene Mutations

Patients with Prader-Willi syndrome are characterized by hyperphagia, hypotonia, developmental delay, hypogonadism, and short stature (234). In these children, obesity may start during the first year of life and becomes prominent by the second year, which in the presence of hyperphagia can result in morbid obesity. They show extreme elevations of Ghrelin, the hunger hormone (235). It was previously suggested that a low metabolic rate caused the obesity in these children (236). However, it has been demonstrated that a lower energy requirement of these children is due to less FFM and not to an unusually low metabolic rate (237). Translocation or deletion of chromosome 15 q11-q12 uniparental maternal disomy, has been reported in about 50 of these patients (238).

Neuroanatomical Findings Associated With Depression

Regions are likely involved (1) frontal lobe areas which are involved in executive functioning, cognitions (hopelessness, guilt) and motivation (2) hypothalamus which mediate neurovegetative symptoms including appetite, sleep, energy metabolism, and autonomic functioning (3) hippocampus and amygdala, involved in the formation and storage of memories. These areas have indeed received attention. Discrepant study findings have occurred and may be attributed to several factors, including variations in study populations (medicated vs. untreated, unipolar vs. bipolar samples, younger vs. older subjects), scan parameters (such as scan thickness), and inclusion of anatomic areas that are difficult to delineate (such as the amygdala). Nevertheless, several consistent findings have been reported.

Effects of Estrogen on Risk Factors for Diabetes

These data are encouraging and suggest important metabolic effects of hormone therapy. However, the results of this posthoc analysis of the HERS study are not definitive and require confirmation in a formal clinical trial. The authors do not recommend the use of HRT for diabetes prevention but encourage further study of the issue.

Diet and Modification of Nutrient Absorption

A more accurate assessment of the caloric needs may be achieved by using appropriate formulas to calculate the rest metabolic rate (RMR), such as those of Harris & Benedict which are based on weight, height, age and sex. Since subjects of the same weight but of different height have similar RMR, formulas may be simplified by considering only weight, age and sex. RMR should be increased by 30, 50 or 70 for low, medium or high levels of physical activity. Table 2 shows the caloric requirement according sex and age for selected weights and activity levels, based on similar formulas.

Dietary and lifestyle alterations

Intake by the order of 20 per cent. (Prentice et al., 1986). The energy intake required to maintain body weight is best estimated by using standard formulae derived from metabolic rate measurements and appropriate reductions in intake advised by altering proportions of foodstuffs in the diet.

Mechanisms Contributing To Brain

The role of insulin in peripheral energy metabolism has been well described, and converging evidence has identified a role for insulin in central nervous system functions. Epidemiological studies support an important relationship between diabetes and other insulin-resistant conditions, and cognitive

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.

Causes Of Insulin Resistance

Insulin resistance may be caused by rare genetic defects that alter insulin binding to its cellular receptors or cause defects in receptor or postreceptor signal trans-duction (1). Recently, defects in the nuclear receptor, PPARy, have also been linked to syndromes of severe insulin resistance (2). In addition, some endocrine-metabolic syndromes, such as Cushing's syndrome, acromegaly, and polycystic ovary syndrome, are associated with insulin resistance because of the hormonal imbalances associated with these conditions. However, in the most common forms of insulin resistance, single gene defects have not been identified and the development of insulin resistance represents a complex interaction among a poorly understood array of predisposing genetic factors and acquired environmental factors that modify insulin sensitivity. Among the latter, the most prominent are obesity (particularly intra-abdominal obesity), physical inactivity, and increasing age. It is also now well documented...

Dietary nutrient composition in type diabetes

Aetiological factor in susceptible individuals. Excess dietary fat is more easily converted to adipose tissue lipid stores than carbohydrate (Flatt, 1985) diet-induced thermogenesis is less with fat than carbohydrates or protein thus inducing lower metabolic rates with high fat diets (Lean and James, 1988 Lean et al., 1989) dietary fat has minimal effects on both appetite and satiety (Caterson and Broom, 2001) hyperinsulinaemia has been associated with high fat intakes possibly through components of the hormonal enteroinsular axis (Grey and Kip-nes, 1971). The associated hyperinsulinaemia will favour further fat deposition and aggravate the insulin resistance of type 2 diabetes, increasing the associated metabolic dysregulation, e.g. dyslipidaemia (Figure 6.3).


The energy costs of pregnancy show wide interindividual variation, but the measured energy intake during pregnancy does not account for the calculated increased energy requirements of pregnancy. It is likely that the mother makes adaptations in energy expenditure in response to pregnancy. The degree of obesity prior to pregnancy influences the maternal metabolic response to pregnancy possibly via a leptin-mediated mechanism. Glucose intolerance does not influence the adaptation of maternal energy metabolism to pregnancy. The large variability in energy costs makes compilation of guidelines for recommended energy intake during pregnancy very difficult (16). Fat gain during pregnancy is highly variable, and there is neither consensus regarding the timing of fat deposition nor regarding whether it is accumulated in subcutaneous or visceral depots. Adipose tissue function per se is unaffected by pregnancy. There is no strong evidence that obese or glucose-intolerant pregnant women...

The Warburg Effect

Over eight decades ago, Otto Warburg 37 discovered that many tumors exhibit a high rate of glycolysis under aerobic conditions - a phenomenon known as the Warburg effect. He identified a particular metabolic pathway in carcinomas characterized by the anaerobic degradation of glucose even in the presence of oxygen (aerobic glycolysis) that leads to the production of large amounts of lactate. Warburg 37 originally hypothesized that the cause of cancer is primarily a defect in energy metabolism. This hypothesis was based on the observation, repeated and verified many times ever since, proving that cancer cells show clear differences in energy metabolism when compared to normal cells. Although Warburg's hypothesis has been declared for obsolete by the concept of carcinogenesis (including the discovery of oncogenes and tumor suppressor genes), his original interpretations still have their significance, and recent discoveries concerning the participation of mitochondria in the phenomenon of...


L-carnitine is an essential co-factor in fatty acid and energy metabolism and recent work suggests that it might be effective in reducing the erythropoetin requirements for controlling anaemia. The US Food and Drug Administration department have recently approved its use in the prevention and treatment of carnitine deficiency in HD patients. Currently, however, there is insufficient evidence to support its routine use in such patients (29).

Who Is At Risk

The metabolic studies in infants cited above (199-202), which tried to identify alterations in metabolic rate that may contribute to future obesity, were inconclusive due to methodology limitations. Recent improvements in indirect calorimetry technology have enabled more accurate measurements of infant energy expenditure. With the new Enhanced Metabolic Testing Activity Chamber (EMTAC), validated for accurate measurements of the components of energy expenditure, such as resting and sleeping metabolic rates, along with physical activity, in infants (203,204), the relationship between maternal obesity and infant feeding-interactions was studied (205). Infants born to obese mothers consumed more energy more rapidly, and more energy as carbohydrate than normal-weight counterparts. Most of the increased intake was from complementary feedings. Furthermore, obese mothers spent less time interacting and feeding their infants who slept longer. However, there were no differences in total daily...

Physical activity

Physical activity has also been shown to reduce obesity and central fat distribution in short-term clinical studies91. As physical activity patterns in free living populations are complex, so is the assessment of physical activity in epidemiological studies91. Many have used questionnaires to assess leisure-time physical activity, which in many urban populations is the primary determinant of differences in energy expenditure between individuals. This is not the case in rural populations, where a more comprehensive evaluation of work activities is required92,93. More exact measures are needed to account for all components of total energy expenditure (including resting metabolic rate and the thermic effect of food), but these are not feasible in large populations over extended periods of time91. A number of review papers91,93-98 and an NIH consensus statement99 have summarized prior work on physical activity.

Energy Balance

Obesity is a heterogenous group of disorders that result from an energy imbalance over an extended period of time in which energy intake exceeds expenditure. It is superficially apparent that obese subjects ingest more food relative to their needs. However, it has long been debated if calorie intake differs between overweight and normal-weight individuals (359,360), suggesting that obese subjects have ''increased metabolic efficiency.'' They may expend relatively fewer calories to maintain body weight due to loss of lean body mass (361,362) resulting from repeated weight reduction attempts that lead to alterations in body composition and decreased FFM. However, there have been multiple attempts to elucidate if there is an intrinsic alteration in metabolic rates that sets the stage for the development of obesity (363). The main determinant of basal metabolic rate (BMR) is FFM and the main determinant of energy expenditure is physical activity. It is believed that minor alterations in...

Energy expenditure

Energy expenditure includes BMR, the thermogenic effect of food (TEF) and physical activity. BMR is the main component of energy expenditure in the average person and is the energy expenditure for maintenance processes. BMR is measured under very strict laboratory conditions that include a 12-h fast and rest, making early morning a good time to make such measurements. Any measure to estimate BMR not made under such strict conditions is referred to as resting metabolic rate (RMR). Energy expenditure associated with physical activity is quantified and discussed in the literature in various forms using energy units such as the kilocalorie or the Joule (SI unit) and other dimensionless quantities which are multiples of BMR (the PAL or the MET). Although the Joule is the SI unit of energy, the kilocalorie is still in common use partly because of the physics related to its definition and mostly because of its use in everyday life in terms of dieting (i.e. calorie counting). There are 4186 J...

Cerebral Adaptation

When hypoglycaemia occurs, the stimulus for counterregulation appears to be a fall in the cerebral metabolic rate of glucose. Boyle et al. (1994) measured arteriovenous differences in glucose concentration in the human brain during hypoglycaemia to show that the rate of uptake of glucose (and by implication of metabolism) falls before most of the counterregula-tory responses and cognitive changes occur. They also demonstrated that this fall in metabolic rate of the brain was reduced in healthy volunteers who were made acutely hypoglycaemic following a period of 56 hours of protracted moderate hypoglycaemia, suggesting that the metabolism of the human brain can adapt to prolonged exposure to low blood glucose. This enables the brain to maintain its metabolism and continue to function in response to subsequent hypoglycaemia. A further study in diabetic patients showed that diabetic patients with strict glycaemic control and impaired awareness of hypoglycaemia were able to maintain the...


Although in the Palaeolithic era hunting and gathering must have been approached at a physiologically bearable pace, Hayes et al. (16) have suggested that they had a very high physical activity level (PAL). The PAL is the total daily energy expenditure divided by basal metabolic rate. The PAL in Palaeolithic times was estimated to be 3.2, a value no contemporary population can aspire to. Present foraging groups have much lower PALs ranging from 2.1 to 1.4 while simple agriculturist societies have PALs that range from 2.3 to 1.5 (17). This compares with PAL values ranging between 2.2 and 1.2 among urban populations in industrialized societies. These and many other observations support the idea that low energy expenditure by contemporary adult dwellers of industrially advanced urban locations contributes to the epidemic prevalence of obesity.


Carbohydrates22'23 are the body's main energy source 50-55 per cent of the daily caloric intake should be provided by them. It is important that people with either type 1 or type 2 diabetes consume the right amount of carbohydrates, as they are the primary energy source for the central nervous system which depends on blood glucose. Carbohydrates also have the role of 'protein sparer', preventing the use of proteins for energy purposes, allowing them to perform their real role in tissue building and as metabolic primers for fat metabolism. The amount of carbohydrates in the diet regulates the levels of the intermediate products of fat metabolism, ketones. If the amount of carbohydrates is too low or unavailable, fat is oxidized for energy purposes with an increase of ketones

Gene expression

Since genes are transcribed to RNA, RNA is translated into proteins, and defects in proteins cause disease, the ultimate goal would be to carry out a random search of expressed proteins in target tissues. This may not yet be completely feasible but the study of large-scale transcript profiles is. This approach has been successful in defining prognoses of cancers but for complex diseases affecting many target tissues it may not be that simple. Also, defining what is differentially expressed among more than 20,000 gene transcripts on a chip is a statistical challenge. Despite these problems, analysis of gene expression in skeletal muscle of patients with type 2 diabetes and prediabetes has provided new insights into the pathogenesis of the disease. It required, however, the analysis of coordinated gene expression in metabolic pathways rather than of individual genes. This is based upon the assumption that if one member of the pathway shows altered expression, this will be translated...

And Atherosclerosis

In patients with DM, and thus in patients with well-defined increased risk for cardiovascular events (12). Fibrates are used to treat patients with increased triglycerides and low HDL, a profile with increased cardiovascular risk often seen among patients with insulin resistance if not frank diabetes (18). Theoretically, PPAR agonists could have vascular benefits based on their various metabolic effects improving insulin sensitivity, lowering glucose, and raising HDL. An alternative but not mutually exclusive hypothesis would be that if PPARs are expressed in vascular and inflammatory cells, then PPAR agonists could have direct effects that might influence atherosclerosis (4). Indeed, this issue has become an area of considerable interest. All PPAR isoforms are now known to be expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and monocytes macrophages and T-lymphocytes (28,29). An increasing amount of data continues to identify various PPAR-regulated target...


An anti-parasitic agent used to treat infections with Pnemocystis carinii (107). It is well known for causing hypoglycemia, IGT and overt DM (108). Diabetes has been observed in more than 100 patients, sometimes with ketoacidosis or lactic acidosis (109-114). Hypoglycemia and diabetes have also been reported after pentamidine isethionate (115) and pentamidine aerosol therapies (116,117). Inappropriate plasma insulin levels were sometimes determined they were excessive in the presence of hypoglycemia, and lower than normal in the diabetic patients treated with pentamidine (110). It has been suggested that a dose-dependent toxicity of pentamidine to the islets of Langerhans can account for these opposite adverse metabolic effects an early excessive insulin leakage from lesioned B-cells as a cause of hypoglycemia, and then B-cell death and insulinopenia causing diabetes.


The prognostic benefits of beta-blockers following myocardial infarction in patients with myocardial infarction are described in Chapter 4. A retrospective analysis of the prognostic effects of beta-blockers in 2723 patients with diabetes and stable CHD was performed as part of the Bezafibrate Infarction Prevention (BIP) study (Jonas etal., 1996). About one-third of the diabetic patients were categorised as receiving chronic beta-blocker therapy, mostly cardioselective. There was a significant 44 reduction in mortality in the beta-blocker group, with a 42 reduction in cardiac mortality. The low use of beta-blockers in diabetic subjects with CHD has been demonstrated in several registries, and probably reflects erroneous fears about hypoglycaemia in this group of patients. Hypoglycaemia is uncommon in diabetic patients with CHD as many of these patients have severe insulin resistance. If hypoglycaemia occurs cardioselective beta-blockers may slightly reduce the symptoms of...


The balance of current evidence suggests that rather than CRP itself, upstream cytokines may be causally linked to vascular risk, since in addition to their role in regulating immune responses, cytokines mediate numerous metabolic effects. Cytokine-induced metabolic effects, which include transient alterations in lipids and peripheral insulin resistance, are favourable in the short term and function as part of the host response to infection and acute inflammation to target specific metabolic fuels to and from essential organs (Sattar etal., 2003a). However, when these alterations are sustained, even if subtly elevated (as in obesity or in patients with diabetes), they appear to be deleterious and may promote accelerated atherogenesis via aggravation of several risk factor pathways, including lipoprotein metabolism, endothelial dysfunction and insulin resistance. Indeed, CRP concentration in population studies correlates with levels of many classical and novel coronary heart disease...


Leptin is secreted and predominantly produced by adipose tissue, which circulates in the blood as a protein of 146 amino acids with a molecular mass of 16kDa (Zhang et al., 1994 Madej et al., 1995). Leptin is presently viewed as a hormone that adapts and responds to metabolic effects on peripheral tissues as well as a satiety signal. Data presently suggests that leptin regulates energy expenditure mainly by acting on the brain. Leptin is actively transported across the blood-brain barrier and reaches the hypothalamus where it binds to specific leptin receptors located on the surface of neuropeptide Y, a tyrosine-containing peptide with powerful stimulatory effects on appetite. This leads to suppression of appetite, and ultimately activates the release of noradrenaline from the sympathetic nerve terminals that innervate adipose tissue and influence insulin actions in adipose tissue, liver, pancreas and potentially reproductive organs (Lonnqvist et al., 1999). The central action of...


In diabetic patients, P-blockers are used mostly in patients with coexisting CAD and congestive heart failure (99). Despite their potential adverse metabolic effects, P-blockers have been proven to have significant favorable effects on CVD outcomes in hypertensive diabetic patients, especially in those with ischemic heart disease and congestive heart failure (CHF) (35). Therefore, these agents should be included in the antihypertensive therapy in diabetic patients, specifically those with CAD and CHF.

Boost Your Metabolism and Burn Fat

Boost Your Metabolism and Burn Fat

Metabolism. There isn’t perhaps a more frequently used word in the weight loss (and weight gain) vocabulary than this. Indeed, it’s not uncommon to overhear people talking about their struggles or triumphs over the holiday bulge or love handles in terms of whether their metabolism is working, or not.

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