Lose Weight By Controlling The Fat Storage Hormone

The Beta Switch Weight Loss Program by Sue Heintze

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Cortisol and Growth Hormone

Growth hormone (GH) and Cortisol are thought to become important glucose-raising hormones only after hypoglycaemia has been prolonged for more than one hour. However, defects in Cortisol and GH release can cause profound and prolonged hypoglycaemia because of a reduction in hepatic glucose production and, to a lesser extent, by exaggeration of insulin-stimulated glucose uptake by muscle. Abnormalities in growth hormone and cortisol secretion in response to hypoglycaemia are characteristic of long-standing type 1 diabetes, affecting up to a quarter of patients who have had diabetes for more than ten years. In rare cases, coexistent endocrine failure such as Addison's disease or hypopituitarism also predisposes patients to severe hypoglycaemia. Pituitary failure, although uncommonly associated with type 1 diabetes, occasionally develops in young women as a consequence of ante-partum pituitary infarction. As an intact hypothalamic-pituitary-adrenal axis is important for adequate...

Ectopic fat storage fat content in obesity

Positive energy balance produces an excess of triglyceride with storage in the liver (Ryysy et al., 2000) and skeletal muscle (Goodpaster and Kelley, 1998 Goodpaster et al., 1997, 2000 Shulman, 2000) which is subsequently followed by insulin resistance, glucose, intolerance and diabetes. This similar effect is also observed in patients with lipodystrophy characterized by a severe reduction in adipose tissue with increased triglyceride storage in the liver and skeletal muscle (Robbins et al., 1979, 1982) and subsequent type 2 diabetes disease. These observations suggest that in either the obese or lipodystrophic state, adipose tissue mass is unable to sequester dietary lipid away from the liver, skeletal muscle or the pancreas. As a result, too much or too little adipose tissue mass leads to ectopic fat storage and may further predispose individuals to insulin resistance and finally type 2 diabetes (Figure 4.3). The failure of pre-adipocytes to proliferate and or differentiate may not...

Leptin

Increased adiposity leads to increased leptin production in fat tissue. Leptin decreases feeding behavior and encourages weight loss (246). Leptin stimulates neurons in the arcuate nucleus of the hypothalamus that coexpress the anorexigenic hormones such as a-MSH, a cleavage product of POMC and cocaine- and amphetamine-regulated transcript (246). Leptin also inhibits neurons in the arcuate nucleus that coexpress the orexigenic hormones, agouti-related protein, and neuropeptide Y (NPY). The neurons in the arcuate nucleus project to other regions of the hypothalamus (including the paraventricular nucleus and the lateral hypothalamic area-parafornical area), where a-MSH binds to its receptor, MC4R, resulting in an upregula-tion of anorexigenic effectors and a downregulation of orexigenic effectors. Bouret et al. examined the effect of leptin deprivation and leptin administration upon the density of the neural projections between the arcuate nucleus and the paraventricular nucleus,...

Cortisol

Increased exposure of fat tissue to cortisol may influence its mass and distribution (107). This is clearly evident in Cushing's syndrome, in which alterations of the hypothalamic-pituitary-adrenal axis leading to cortisol hypersecretion create a phenotype of abdominal obesity, dyslipidemia, insulin resistance, and hypertension (108). Common abdominal obesity obviously shares the latter features, although more subtle alterations of cortisol activity have been documented. Specifically, plasma cortisol levels are normal in abdominal obese subjects (107), but the sensitivity and drive of the hypothalamic-pituitary-adrenal axis have been shown to be increased in some studies (109, 110). Urinary free cortisol levels are also elevated and the cortisol circadian rhythm is flattened (111). In addition to these features, increased peripheral cortisol synthesis by 11b-hydroxysteroid dehydro-genase (HSD) is now clearly emerging as perhaps the most significant hormonal alteration in patients with...

Factors modifying the relationship between obesity and diabetes

Whilst obesity is clearly important, other factors appear to influence the susceptibility both to weight gain and to the development of diabetes. The 'thrifty' gene hypothesis (Neel, 1962) suggests that the obese-type 2 diabetes mellitus genotype may have had some survival advantage, perhaps by favouring fat storage at times when food was abundant, so leading to improved survival during famines. However, this hypothesis remains an epidemiological explanation, with the exact genetic factors remaining unclear and no prospective data showing a survival advantage in subjects felt to have a thrifty genotype. Much recent discussion has centred on the potential importance of the in utero environment in the causation of later type 2 diabetes (Hales and Barker, 2001). This hypothesis, the 'thrifty' phenotype hypothesis suggests that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes results from the effects of poor nutrition...

T Bobbert and Joachim Spranger contents

Obesity is among the most frequently encountered metabolic diseases worldwide. Moreover, its incidence and prevalence are rising rapidly.1,2 More than half the world population is considered overweight.3 Being overweight constitutes a health risk because it is associated with several co-morbidities including dyslipidemia, hypertension, type 2 diabetes, and atherosclerotic cardiovascular disease.45 Adipose tissue was initially believed to be only a fat storage organ, but it is now acknowledged to be an active participant in energy homeostasis and other physiological functions. Adipose tissue is known to express and secrete a variety of novel adipocytokines that have been implicated in the development of insulin resistance and atherosclerosis.6,7 Dysregulation of adipocytokine production is directly involved in the pathophysiology of metabolic syndrome, and normalization of plasma concentrations of adipocytokines reverses the phenotype of metabolic syndrome.8,9

Evaluating obesityrelated hypotheses for progression of type diabetes

Mechanism as this fat depot does not drain into the portal vein. Furthermore, insulin resistance appears independently by an increased truncal subcutaneous adipose tissue and an increased visceral fat store (Albu et al., 2000 Marcus et al., 1999 Bavenholm et al., 2003). Because of growing evidence that subcutaneous fat may play an important role in obesity-related type 2 diabetes with conflicting evidence for the role of the portal fat, changes in the model for the understanding of adipose tissue in the pathogenesis of type 2 diabetes have been proposed (Kuhn, 1962). The two emerging models are 'the ectopic fat storage syndrome' and to view the adipocyte as an endocrine organ (Ravussin and Smith, 2002).

Effects On Adipose Tissue

The thiazolidinediones, through PPAR-y activation cause preadipocytes to differentiate into mature fat cells and also induce key enzymes involved in lipogenesis (56). However, in vitro studies demonstrate that the thiazolidinediones specifically promote the differentiation of pre-adipocytes into adipocytes only in subcutaneous fat and not in omental fat (57). Thiazolidinedione-associated increase in fat mass occurs predominantly in the more insulin responsive subcutaneous fat depots and not in the insulin-resistant visceral body compartments which secrete increased quantities of cytokines. Early clinical studies with CT scans confirmed that thiazolidinedione treatment produces a shift in adipose tissue distribution from the more deleterious omental depot to the more insulin sensitive subcutaneous compartment (58,59). Recent studies with determinations of fat distribution using abdominal magnetic resonance imaging (MRI) and dual energy x-ray absorptiometry (DEXA) after...

Adipose Tissue as an Endocrine Organ

Obesity is the result of an increase in adipocyte size (fat storage) and number (115, 116). Obesity can be interpreted based on our current understanding of fat biology as a pathological enlargement by fat cells and a failure to adequately proliferate and differentiate in response to excessive energy intake (117-121). In addition to surplus energy, hypertrophic fat cells are challenged by chronic inflammation and perhaps insulin resistance itself, posing considerable stress to its various organelles. Among these, recently the role of the endoplasmic reticulum (ER) has been highlighted as a vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance (121). Under normal conditions, the ER physiologically adapts to meet the demands related to protein and triglyceride synthesis in the differentiated fat cell, but when nutrients are in pathological excess, this overwhelms the ER activating the unfolded protein response (UPR) and...

Steroid Hormones And Body Fat Distribution Patterns

We still know little about the etiological factors leading to preferential deposition of intra-abdominal fat in the presence of excess energy intake. It is widely believed that sex hormones and more generally steroid hormones play a key role in the regulation of body fat distribution (106). However, their specific influence on fat cells has remained elusive, especially in humans. The following section will address the role of steroid hormones, namely cortisol, androgens, and estrogens in the appearance of sex-specific adiposity patterns.

The Inflammation Syndrome Connection

The high-sugar and high-carbohydrate diets that lead to obesity raise glucose levels, and elevated glucose spontaneously generates large numbers of free radicals. These free radicals stimulate the inflammatory response, which can increase the risk of coronary artery disease, cancer, Alzheimer's, and many other diseases. In addition, abdominal fat cells secrete large quantities of pro-inflammatory interleukin-6 and C-reactive protein. In overweight and obese people both of these substances help maintain a state of chronic inflammation. Increases in body fat are often associated with disturbed hormone levels such as elevated cortisol and insulin and decreased thyroid hormones. Sometimes figuring out which came first is like the chicken-or-the-egg story. However, being overweight leads to hormonal shifts that make it easy to gain still more weight. Because of their cell-regulating actions, it is very likely that weight-promoting hormones increase the activity of pro-inflammatory...

Pregnancy an inflammatory insulinresistant state

Profound metabolic adjustments occur during pregnancy to assure an adequate nutrient supply is available to support fetal growth. Since glucose is the preferred fuel of the fetus, maternal metabolism is shifted toward a hyperglycemic state. This ensures facilitated glucose diffusion from maternal circulation across the placenta to the fetus. Maternal hyperglycemia is created by establishing an insulin-resistant state. Maternal insulin resistance increases throughout gestation, reaching a peak in late gestation when fetal fuel demands are the highest.12 The rise in insulin resistance is ascribed to alterations in maternal cortisol levels and placental hormones (human placental lactogen, progesterone, and estrogen).12 However, the changes in insulin resistance have never been correlated with these hormonal changes in a prospective, longitudinal study.13 The recent evidence that adipokines such as TNF-a and leptin affect insulin sensitivity in non-pregnant individuals has led...

Understanding hypoglycemic unaWareness

If your child suffers from hypoglycemic unawareness, he doesn't feel the warning adrenergic symptoms that alert him that his blood glucose is too low. He may have a reduced or no adrenaline response as well as a reduced cortisol and growth hormone response this means that nothing is raising his blood glucose as it falls. Without the warnings of palpitations, anxiety, and hunger,

Etiology Of Hyperglycemia In Acute Ischemic Stroke

Critical illnesses, including stroke, are accompanied by a generalized stress reaction with the activation of the hypothalamo-hypophyseal-adrenal axis (HPA axis). This activation leads to a subsequent increase in glucocorticoids (cortisol), and the activation of the sympathetic division of the autonomic nervous system, resulting in an increase in catecholamines (22). Indeed, in the acute phase till the first week after stroke, increased levels of cortisol and catecholamines have been shown since the 1950s (23,24). Stress hormones are known to enhance both glycogenolysis and gluconeogenesis

What are the effects of hypoglycaemia

Decrease in the plasma glucose level is initially accompanied by stimulation of the autonomic nervous system, as well as of various hormones compensatory to insulin (glucagon, catecholamines, growth hormone, cortisol). Afterwards, if blood glucose continues to decrease, neuropsychiatric manifestations occur. Compensatory hormones are secreted from a plasma glucose level of 65 mg dl (3.6mmol L). At the same time, from a level of 70 mg dl (3.9 mmol L), insulin secretion from the pancreas, in normal people, has started to decrease significantly (up to the level of complete cessation). Glucagon and adrenaline (epinephrine) are secreted immediately and act quickly, whereas the actions of cortisol and growth hormone are slow

Etiology And Precipitating Factors

Insulin deficiency and increased counter-regulatory hormone secretion (i.e., glucagon, growth hormone, catecholamines, and cortisol) underlie the basic mechanism leading to DKA in patients with diabetes. If insulin is present, lipolysis and the development of ketoacidosis are prevented. The most common precipitants of DKA are infections (such as pneumonia and urinary tract infection) and insulin omission or under-treatment (13). Other

Rationale For Control Of Blood Glucose

Normal metabolism should be mimicked as closely as possible. Therapeutic goals include the avoidance of hypoglycemia, hyperglycemia, lipolysis, ketogenesis, proteolysis, dehydration, and electrolyte imbalance. Type 1 diabetic patients should receive a continuous supply of insulin to avoid ketosis. Sufficient insulin should be supplied to counterbalance the hyperglycemic effects epinephrine, norepinephrine, cortisol, glucagon, and growth hormone

What Else Might Help

Finding some means of stress reduction or stress management is important as well. Stress raises levels of cortisol, which in turn boosts insulin levels contributing to an increased risk of both abdominal obesity and heart disease. Removing yourself from the stress, even temporarily, can have an extraordinary effect. Consider a daily walk (which also lowers glucose and insulin levels), meditation, a hobby, recreational reading, or sightseeing as stress-reducing activities.

Tight glycaemic control and the effects of antecedent hypoglycaemia

The increased risk of hypoglycaemia appears to be due to periods of antecedent hypoglycaemia that usually accompanies intensification of treatment. The changes appear similar to those observed with increased disease duration with a resetting of the threshold for activation of the autonomic response and symptoms to a glucose level below rather than above that for cognitive dysfunction. The site and precise nature of the abnormality are unknown but presumably the cerebral pathways responsible for sensing and activating the autonomic response are disrupted. This might be due to adaptation to hypoglycaemia within the central nervous system or possibly modulation by one of the counter-regulatory hormones. Cortisol is known to have powerful effects on neuronal function and infusing cortisol to levels seen during hypoglycaemia can produce impaired hormonal responses and symptoms in response to subsequent episodes. Thus, recurrent hypoglycaemia can produce a vicious circle of reduced...

Hypoglycaemic stimuli for research Insulin tolerance test

Most experimental hypoglycaemia is induced by insulin. An intravenous insulin challenge, called the insulin tolerance or insulin stress test, was the first test used to determine the effect of hypoglycaemia (Dell'acqua 1951 Hanzlicek & Knobloch 1951). This method was used in early studies that identified the role of the adrenal gland in protective responses to hypoglycaemia (Vogt 1951 De Pergola & Campiello 1953) and has also been used in the past to induce hypoglycaemic seizures as a treatment for severe depression (Mueller et al. 1969) and as a stimulus for gastric acid secretion in the standard Hollander test assessing the completeness of vagotomy (Colin-Jones & Himsworth 1970). It is still used to determine pituitary reserve for growth hormone and cortisol release. Prior to performing an insulin tolerance test, it is important to rule out complete deficiency of counterrgulatory hormones and establish cardiovascular status. A 9 am cortisol, baseline thyroid function and...

Adjusting Your Insulin for Time Changes

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

Myocardial Infarction

Only a few cases have been published of myocardial infarction and hypoglycaemia in diabetic patients (Purucker et al., 2000 Chang et al., 2007). This possible association is very difficult to establish because of the problems described above. In addition, the release of stress hormones such as glucagon, cortisol and epinephrine will raise blood glucose and make the contribution of preceding hypoglycaemia almost impossible to confirm.

When counterregulatory hormones are released

As the blood glucose falls, it stimulates release of adrenaline, noradrenaline, glucagon, cortisol, and growth hormone. Adrenaline causes tachycardia with palpitations and tremor. Glucagon released from the pancreatic islet cells stimulates glucose release from the liver. However, in people with diabetes the glucagon response may be blunted or absent and excess insulin inhibits liver glucose release. The 'emergency' hormonal response to hypoglycaemia is called counter-regulation.

Physiological actions of glucagon

Although insulin is the main glucose-lowering hormone, a number of humoral factors may increase blood glucose concentrations, including glucagon, catecholamines, cortisol, and growth hormone. Glucagon is a peptide hormone released by a-cells of the pancreas in response to drops in blood glucose concentration. In vivo experiments in dogs have shown that glucagon secretion increases twofold in response to a fall in glucose from 100 mg dl (5.6 mmol l) to 80 mg dl (4.5 mmol l).5 The principal target organ of glucagon action is the liver, in which it increases glycogenolysis and gluconeogenesis and inhibits glycogenesis and glycolysis.* Glucagon acts via hepatic cell surface G-protein-coupled receptors by a number of intracellular mechanisms whose net result is that hepatic glucose production increases and blood glucose rises. Increasing evidence suggests that, in type 2 diabetes, hyperglucagonemia and or an imbalance between the glucagon insulin ratio is present.6

Insulin secretion in individuals without diabetes

Both basal and nutritional insulin requirements vary considerably throughout the day, as well as from day to day. Nutritional insulin requirements vary primarily depending on the quantity, composition, and timing of food. Basal requirements tend to decrease with exercise and increase with stress or illness. Basal insulin requirements also may increase as the result of the dawn phenomenon, which has been attributed to morning rises in growth hormone and cortisol levels.

Understanding your body mechanics during exercise

With exercise, insulin levels in nondiabetics and people with type 2 diabetes decline, because insulin acts to store and not release glucose and fat. Levels of glucagon, epinephrine, cortisol, and growth hormone increase to provide more glucose. Studies show that glucagon is responsible for 60 percent of the glucose, and epinephrine and cortisol are responsible for the other 40 percent. If insulin did not fall, glucagon could not stimulate the liver to make glucose.

Metabolic Consequences Of Surgery In Type Diabetes

Surgery and, to a lesser extent, general anesthesia represent major stress with the release of adrenocorticotropic hormone (ACTH), cortisol, growth hormone, catecholamines, and glucagon. The magnitude of these counterregulatory responses is related to the severity of surgery (1-3) and the presence of complications such as sepsis. Hyperglycemia attributed to the concomitant hypersecretion of catecholamines, glucagon, and cortisol has even been described in nondiabetic humans during periods of severe surgical or medical stress (8-10). Routine abdominal surgery such as hysterectomy raises plasma epinephrine and norepinephrine concentrations threefold (11). Elevation of these individual hormones does not cause marked alterations in fasting plasma glucose concentrations in normal subjects. However, a simultaneous infusion of all three hormones at concentrations that reproduce circulating levels occurring in major illness causes marked hyperglycemia in healthy volunteers (12). Increases in...

EGIR European Group for Insulin Resistance

Nevertheless, steroid hormones play an exceptional role. Glucocorticoids, specifically increase intra-abdominal adipose tissue synthesis, whereas female hormones promote fat accumulation on the buttocks and thighs. Generally, in android type obesity, insulin resistance, hyperinsulinaemia, small increase in cortisol and androgen levels is seen, the latest regarding only women. Apart from cortisol levels (which most of the time are within normal limits), a significant role is exerted by the intracellular activity of active cortisol, determined by the concentration of the enzyme 17-HSD1( 17-hydroxy-steroid dehydrogenase-1). The activity of this enzyme is increased in the intra-abdominal fat of persons with central obesity and the metabolic syndrome. According, however, to the neuroendocrine theory of obesity (Bjorntrop, 1992), the central accumulation of adipose tissue and appearance of resistance to the action of insulin are due to an increased activity of the...

Counterregulation

Glucagon, growth hormone and Cortisol were similar. Other studies, using intravenous bolus injection or infUsion of insulin to induce hypoglycaemia, demonstrated that the counter-regulatory hormonal responses were normal in people with Type 2 diabetes (Table 10.8). Meneilly, Cheung and Tuokko (1994b) used a glucose clamp method to lower the blood glucose in a stepwise fashion in older non-obese subjects, 10 having Type 2 diabetes (mean age 74 years) and 10 being healthy non-obese controls (mean age 72 years). At an arterialized blood glucose concentration of 2.8 mM, the subjects with diabetes exhibited lower increments of glucagon and growth hormone, whereas in the non-diabetic subjects the magnitudes of the adrenaline and cortisol secretory responses were higher. betic control group. Over a 12-hour period, the blood glucose recovery was slightly slower in the people with Type 2 diabetes and the maximal responses of gluca-gon, cortisol and growth hormone were 50 lower than those...

Insulin Resistance and Cancer

The cycle of inflammatory chemistry that is activated through chronic stress and cortisol release, leaky gut, environmental stressors (such as chemical preservatives, plastics, and heavy metals), obesity, thyroid dysfunction, and immune system imbalances causes chronic imbalances in blood glucose homeostatis, eventually lead to type 2 diabetes. This progression to diabetes and its metabolic consequences has also been linked in clinical studies with the development of cancer 7, 8 . Researchers have known for decades that cancer cells consume more glucose than normal cells. All cells use both oxidative phosphorylation and glycolysis pathways for energy (ATP) but rely overwhelmingly on oxidative phosphorylation, switching to glycolysis at times of oxygen deprivation. Cancer cells, however, have been reported to exhibit increased glycol-ysis due in part to mitochondrial respiration injury and hypoxia. A shift in energy production from oxidative phosphorylation to glycolysis - the...

Identifying The Responsible Cellular Event

Insulin resistance is also frequently observed in clinical conditions associated with overproduction of counter-regulatory hormones such as cortisol, epi- nephrine, and growth hormone (6). Specifically, acromegaly, Cushing's syn- drome, and pheochromocytoma, on clinical grounds, are associated with attenuated insulin action and may present with impaired carbohydrate metabolism. A number of other human diseases and conditions characterized by insulin M resistance have been described, as recently reviewed by Hunter and Garvey these J are listed in Table 1 (6). a

Managing Diabetes and Pregnancy

Despite increased first- and second-phase insulin release after a carbohydrate load in normal pregnancy, in the fed state there is a significant reduction in net insulin-mediated glucose disposal by the third trimester. The result is somewhat higher maternal blood glucose levels in nondiabetic subjects, and marked hyperglycemia in inadequately treated pregnant diabetic women. The contra-insulin effects of gestation are related to hPL, progesterone, cortisol, and prolactin, with the defects at the postreceptor level of muscle and hepatic cells. Due to the insulin resistance and enhanced ketogenesis of pregnancy, ketoacidosis is a great danger during gestation. Markedly increased doses of insulin are usually required to control hyperglycemia after the first trimester. Glucagon is well suppressed by glucose during pregnancy, and secretory responses of glucagon to amino acids are not increased above nonpregnant levels.

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...

Counterregulatory Hormone Responses To Hypoglycemia In Women

There is a large sexual dimorphism in counterregulatory responses to hypoglycemia. It has been clearly demonstrated that both healthy young men and women with T1DM have reduced neuroendocrine, ANS, and EGP as compared to age and body mass indexed matched men (39-43). Davis et al. (2000) (43) illustrated that healthy and T1DM women have lower catecholamine, glucagon, cortisol, growth hormone, EGP, and lactate responses compared to age and BMI matched men. On the other hand, women have increased lipolytic responses to hypoglycemia. This sexual dimorphism also occurs during exercise and is not due to differences in glycemic thresholds for activation of counterregulatory responses (43) (Fig. 5).

Calculating glucose thresholds for hormone release

Glucose thresholds for release of counterregulatory hormones or onset of other responses to hypoglycaemia are defined as the plasma glucose concentration at which the response is fisrt significant. They can thus only be reliably identified in slow reductions in plasma glucose, preferably stepped, as described above. The critical issue is to decide before starting what determines a significant change. This can either be to a specific value or by a predefined degree of increase. The gold standard is to perform euglycaemic studies of the same duration in the same patients in the same conditions and compare the hypoglycaemic responses with the eugly-caemic absence of response in each subject. For smaller pilot studies, where this is impractical, some investigators have used a statistical definition such as a change in excess of two standard deviations over the mean basal readings - for this, one strictly requires at least five baseline measures for each subject in order to define the...

Measurement of counterregulatory hormones

The hormonal counterregulatory response to hypoglycaemia is a carefully orchestrated release of hormones that has a natural hierarchy in the non-diabetic individual that protects the individual from severe hypoglycaemia (Mitrakou et al. 1991). The first step is a reduction in insulin production, followed by the release of glucagon, adrenaline, cortisol and growth hormone (Cryer et al. 1989). Samples for glucagon are collected in lithium heparin tubes containing 50 l of trasylol, while cortisol, C-peptide and free insulin are collected in serum tubes. Following immediate centrifugation at 3,000 rpm for 10 minutes, the plasma is decanted of and stored at -80 C before being analysed by radioimmuno assay.

The Placental Barrier to Excess Androgens

The experimental animal research and the clinical observations cited above suggest a common prenatal etiology for the postnatal endocrine metabolic manifestations of PCOS. The potential sources of excess androgens during intrauterine life to account for fetal programming of PCOS in humans, however, are not clearly known and remain an issue for further research. Normally, the female fetus is protected from the effect of maternal or fetal adrenal androgens by a combination of high SHBG that binds androgens and a high level of placental aromatase activity that converts androgens to estrogens. In a similar way, the fetus is also protected from excess maternal glucocorticoids by the feto-placental 11b-hydroxysteroid dexydrogenase type 2 (11b-HSD2), which catalyzes the metabolism of active cortisol to inactive cortisone (59). Thus, the primary function of placental SHBG and aromatase is to maintain the androgen to estrogen balance and protect the female fetus from the high concentration of...

Human Single Gene Mutations

Believed that excessive weight gain in these children is caused by disturbance of hypothalamic appetite center(s), which leads to increased food intake. Pseudo-hypoparathyroidism (Type 1A) (PHP) is also associated with obesity and short stature and is characterized by short fourth metacarpal, short thick neck, rounded facies, mental retardation, and hypocalcemia (240). It is commonly inherited as an autosomal dominant trait and may be accompanied by hypothyroidism and gonadal failure. The gene is located in chromosome 20q13.2. These patients present a germline loss of function mutations in the alpha subunit of the ubiquitously expressed G protein that couples many hormone receptors to the adenylate cyclase second messenger system. The hypothalamic GS protein-coupled melanocortin 4 (MC4) receptor in the hypothalamus, which mediates the effects of leptin on inhibition of satiety as described below. PHP patients present genetic mutations in GS alpha, which result in severe obesity and...

Mechanisms Of Counterregulatory Failure

In blood glucose (White et al., 1985) (Figure 6.10). Thus, patients with type 1 diabetes of long duration are at risk of severe and prolonged neuroglycopenia during hypoglycaemia as a direct consequence of inadequate glucose counterregulation. Although attenuated growth hormone and cortisol responses are less common, they are late manifestations in terms of diabetes duration. The systemic mediator theory suggests that a substance is released in response to hypogly-caemia which attenuates subsequent sympathoadrenal responses to further episodes of hypo-glycaemia. The initial candidate for this was cortisol, based on two observations first, the attenuating effect of antecedent hypoglycaemia on later sympathoadrenal responses is absent in patients with primary adrenocortical failure and second, in healthy volunteers, following infusions of cortisol (to supraphysiological levels) during euglycaemia, adrenomedullary epinephrine secretion and muscle sympathetic neural activity were reduced...

Normal Glucose Counterregulation

This appears to be the result of glycemic thresholds for the epinephrine responses at higher plasma glucose concentrations in children (19,20). The glucagon, growth hormone, and cortisol responses to hypoglycemia are similar in children and adults (18,19). In general, men have greater neuroendocrine and metabolic responses to hypoglycemia than women (21-24). This appears to be the result of greater sensitivity to a given level of hypoglycemia in men because the glycemic thresholds are similar in men and women (23,24). The mechanism(s) of these age and gender differences is not known.

Discovering drugs and chemicals that may cause or Worsen diabetes

There's a long list of drugs and chemicals that may cause diabetes or bring out latent diabetes in a number of different ways. Two of these chemicals are cortisol, which I cover in the earlier section on Cushing's syndrome, and thyroid hormone, which I mention in the earlier section on other hormone-induced causes of diabetes.

Counterregulatory Hormone Responses To Hypoglycemia In Older Adults

Meneilly et al. (44) investigated the effects of age on counterregulatory responses during hyperinsulinemic hypoglycemic clamp studies. They reported that older adults with diabetes had reduced glucagon and growth hormone responses during hypoglycemia, but reported increased epinephrine and cortisol responses when compared to age matched nondiabetic controls. Even with this mixed review, hypoglycemic symptom scores were similar in both the groups at all levels of glycemia (44).

Counterregulation During Hypoglycaemia

That blood glucose starts to rise when plasma insulin concentrations are still ten times the baseline values means that it is not simply the reduction in insulin that reverses hypogly-caemia, but active counterregulation must also occur. Many hormones are released when blood glucose is lowered (see below), but glucagon, the catecholamines, growth hormone and cortisol are regarded as being the most important. Several studies have determined the relative importance of these hormones by producing isolated deficiencies of each hormone (by blocking its release or action) and assessing the subsequent response to administration of insulin. These studies are exemplified in Figure 1.4 which assesses the relative importance of glucagon, adrenaline (epinephrine) and growth hormone in the counterregulation of short term hypoglycaemia. Somatostatin infusion blocks glucagon and growth hormone secretion and significantly impairs glucose recovery (Figure 1.4a). If growth hormone is replaced in the...

What are the acute metabolic and hormonal effects of exercise on the body

During moderate intensity exercise in non-diabetic people, blood glucose levels remain essentially stable. This is due to the fact that hepatic glucose production (through glycogenolysis and gluconeogenesis mentioned above) increases 2-4 fold, to compensate for the increased needs of the exercising muscles. Hepatic glucose production during and after the exercise session is under the direct control of glucagon and insulin and is mainly determined by the molecular relationship of glucagon insulin in the portal vein circulation. If moderate intensity exercise continues for several hours, hepatic glucose production can no longer compensate for the increased muscular utilization and plasma glucose levels tend to decrease. This, in conjunction with the increased insulin sensitivity that exercise produces, leads to a decrease in insulin secretion by the pancreas. In contrast, glucagon levels increase (which promotes glycogenolysis and gluconeogenesis in the liver and lipolysis in the...

The Need To Tightly Control Glycemia

The normal defense mechanisms against hypoglycemia consist primarily of glucagon release from a-cells of the pancreatic islet followed shortly afterward by epinephrine release from the adrenal medulla (2). Cortisol and growth hormone secretion serve more chronic, long-term protective roles. Glucagon released into the portal circulation travels quickly to hepatocytes to induce glycogenolysis, which releases glucose into the systemic circulation via the hepatic vein. Glucagon is normally secreted when circulating glucose levels reach 50-60 mg dL. Soon thereafter, epinephrine is secreted and also stimulates glycogenolysis. In the early stages of diabetes mellitus, patients retain the ability to release glucagon and epinephrine during hypoglycemia. However, within several years, the glucagon response begins to diminish and is then lost in most patients (3). Eventually, the epinephrine response is also compromised although not usually not totally absent (4). The most serious aspect of this...

Components Of The Physiologic Insulin Regimen

Correction- or supplemental-dose insulin is used to treat hyperglycemia that occurs before or between meals despite administration of routine daily doses of basal and prandial insulin, and is taken in addition to these standing doses. When the patient with diabetes is ill or stressed, total daily insulin requirements commonly increase. This increase in insulin requirement is a result of release of insulin counter-regulatory hormones, predominantly cortisol and catecholamines, and to a lesser extent glucagon and growth hormone, which

The risks of conceiving before you have control of TDM

I Respiratory distress syndrome, which is difficulty breathing as a result of a lack of surfactant, a substance made in the lungs that keeps the air tubes open for breathing. Surfactant requires cortisol from the adrenal gland, but the large amount of glucose in the baby's circulation during the pregnancy suppresses the production of cortisol. The more immature the baby, the worse the problem is, so delivering the baby as late as possible is very important.

How does kidney transplantation differ in people with and without DM

The perioperative period is managed with an intravenous infusion of an insulin solution together with frequent blood glucose measurements and prompt adjustment of the solution rate or small additional bolus rapid-acting insulin injections (see Chapter 7 'Surgery in diabetes'). Preoperative problems include the need for hydration restriction, whereas postoperatively, when initially large quantities of fluids are needed, blood glucose should be hourly monitored and insulin administration accordingly adjusted. High blood glucose levels due to cortisol administration are initially treated with large intravenous doses of insulin, and later with an intensive insulin regimen or mixtures of rapid acting and intermediate acting insulin. Steroid-induced diabetes that sometimes occurs in persons without a previous history of diabetes can be managed with antidiabetic pills, provided it is mild. Decrease in steroid doses during the following months makes management easier.

Monitoring the blood glucose

You may think that a sick child should have lower blood glucose, especially if he has nausea and vomiting. This isn't the case, however. Don't assume that your child's blood glucose falls because he can't eat. Illness provokes the body to secrete hormones such as cortisol and glucagon that tend to raise the blood glucose. Illness also increases insulin resistance, so a given amount of insulin doesn't lower the blood glucose as much as usual.

Distinguishing between controlled and uncontrolled glucose

Other hormones besides insulin play an important role as control of glucose is lost. Each tries to raise the blood glucose to satisfy the needs of the tissues. I mention one such hormone, glucagon, from the A cells in the pancreas's islets of Langerhans, in the previous section. In addition, the adrenal glands located above the kidneys begin to secrete two important hormones, adrenaline and cortisol. After a while, the pituitary gland in the brain secretes growth hormone. Following is more information on these hormones Cortisol increases the production of glucose by stimulating the breakdown of both proteins and fats while decreasing the uptake of glucose by tissues that require insulin, like muscles and the liver, to make it available for the brain.

Investigating the pathogenesis of problematic hypoglycaemia

For comparative studies, subjects should be age and gender matched, as there are important differences in counterregulatory responses between sexes and age groups (Matyka et al. 1997 Davis et al. 2000). Mixing genders and ages will at the very least increase the variance of the measures made and may obscure differences resulting from other factors. If groups are of mixed gender in a cross sectional study, the gender distribution must be matched. Vigorous exercise and caffeine should be avoided prior to the study as they can also affect counterregulatory responses (Debrah et al. 1996 Sandoval et al. 2006). Subjects should be studied in the same position (lying or standing) as there is a greater perception of hypoglycaemic symptoms in the standing position than in the lying position (Hirsch et al. 1991). It is usual to study subjects in the fasting or post-absorptive state. This allows a steady-state baseline. In the fed state, symptoms of hypoglycaemia are decreased, but...

Dyslipidaemia and Type Diabetes

With increasing obesity, in particular visceral obesity, fat cells become enlarged and apparently less responsive to insulin, i.e. insulin resistant (Frayn, 2001). Some investigators argue that adipocyte sensitivity to insulin is maintained until well after other organs become insulin resistant but such work generally derives from studies on subcutaneous tissues rather than the generally accepted more relevant visceral

Adipose Tissue and Cytokines

Adipose tissue is also a major source of inflammatory cytokines. The group of You et al. 23 investigated the relationship of abdominal subcutaneous adipose tissue cytokine gene expression to body composition, fat distribution, and metabolic risk during obesity. They determined body composition, abdominal fat distribution, plasma lipids, and abdominal subcutaneous fat gene expression of leptin, TNF-a, IL-6 and adiponectin in 20 obese, middle-aged women and concluded that abdominal subcutaneous adipose tissue expression of inflammatory cytokines is a potential mechanism linking obesity with its metabolic comorbidities. Those inflammatory cytokines secreted from adipose tissue may play an important role in the progression of cancer. While most of the cytokines originate from immune cells, or tumor cells themselves, cytokines secreted from adipose tissue could play a more central role in the treatment of obese patients. The increased release of cytokines from adipose tissue may play a...

Thiazolidinediones the glitazones

Troglitazone, brand name Rezulin (called Prelay outside the United States), was the first oral agent for type 2 diabetes that actually reversed the basic lesion in this disease, namely the insulin resistance. It does this by causing changes within the muscle and fat cells where the insulin resistance resides. These changes take several weeks to occur, and if the patient stops taking troglitazone, they take several weeks to subside.

Staying Healthy for Life

However, I am convinced that the increase in inflammation has accelerated as a consequence of eating a poor or unbalanced diet, a situation others have described as malnutrition on a full stomach. For example, fat cells produce large amounts of inflammation-causing substances, such as interleukin-6 and C-reactive protein. With two-thirds of the population now overweight, it is easy to see how large numbers of people have set the stage for chronic inflammatory diseases.

Obesity and Nutritional Intake

Instead of food intake, the distribution of adipose tissue may be more closely associated with adiponectin. There is a strong inverse correlation between adiponectin levels and visceral or central fat, compared to subcutaneous fat (9,19). In contrast to subcutaneous adipocytes, human omental adipose tissue had a significant negative correlation with BMI, and only it responded to insulin and PPAR-a agonist administration with increased adiponectin production (23). These findings suggest that adipose tissue, particularly in the visceral distribution, may have an inhibitory mechanism for its own production of adiponectin, perhaps mediated by other factors produced by fat cells such as TNF-a (13).

Insulin injection sites

Insulin has a direct effect on fat cells and causes hypertrophy at overused injection sites. These unsightly bulges also cause variability in insulin absorption. Atrophy due to insulin antibodies is rarely seen nowadays. Patients must be encouraged to use the whole extent of each available injection site.

Type Diabetes The Twentieth and Twenty FirstCentury Epidemic

Various factors contribute to insulin resistance being overweight, advancing age, a sedentary lifestyle, an inherited susceptibility, and certain hormonal conditions such as polycystic ovary syndrome. We don't completely understand why insulin resistance develops, and there is probably more than one explanation, but recent research suggests that fat cells produce chemicals that cause tissues to resist the effects of insulin. More fat cells, as in obesity, make more of these chemicals. As a result, sugar can't move into cells and begins to accumulate in the blood, especially after meals. The rising blood-sugar levels drive the beta cells to produce more and more insulin to help push the sugar into the cells where it is needed. And since rising blood-sugar levels also worsen insulin resistance, a vicious cycle begins.

Whole body fat distribution subcutaneous and visceral fat

Even though the total fat mass determines the plasma pool of FFA and thereby the FFA flux from adipose to non-adipose tissue (Lewis et al. 2002), there are differences in the relationship of subcutaneous and visceral fat depots to features of peripheral and hepatic insulin sensitivity (Misra et al. 1997). Visceral fat cells are more sensitive than subcutaneous fat cells to the lipolytic effect of catecholemines and less sensitive to the antilipolytic and fatty acid re-esterification effects of insulin (Kahn & Flier 2000). Furthermore, the venous effluent of visceral fat depots leads directly into the portal vein, resulting in greater FFA flux to the liver. This makes the visceral fat depots more efficient than subcutaneous fat in influencing the carbohydrate metabolism in the human body (Kissebah 1996).

Type Diabetes Management

Your muscle and fat cells often are resistant to the action of insulin. In this case, a regular exercise program and weight loss, often in addition to medication, can help. Your beta cells in the pancreas may not release enough insulin to meet your needs. In this case, sulfonylureas or insulin are helpful. Your liver may release too much glucose. In this case, metformin can be helpful.

The Insulin Receptor Transduction through Tyrosine Kinase

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 glycoinositol derivative that stimulates phosphoprotein phosphatases, may be released at the cell membrane to account for the short-term metabolic effects of insulin. The activated p-subunit also catalyzes the phosphorylation of other members of the IRS family, such as Shc and Cbl. Upon tyrosine phosphorylation, these proteins interact with other signaling molecules (such as p85, and Grb2-Sos and SHP-2)...

Lipoprotein Metabolism

Chylomicrons are assembled in the enterocytes of the small intestine after ingestion of dietary fat (triglyceride) and cholesterol. In the lymph and the blood, chylomicrons acquire several apolipoproteins, including apo C-II, apo C-III, and apo E. In the capillary beds of adipose tissue and muscle, chylomicrons interact with the enzyme lipoprotein lipase (LPL), which is activated by apo C-II, and the chylomicron core triglyceride is hydrolyzed. The lipolytic products, free fatty acids, can be taken up by fat cells where they are converted back into triglyceride, or by muscle cells, where they can be used for energy. Apo C-III can inhibit lipolysis, and the balance of apo C-II and apo C-III determines, in part, the efficiency with which LPL hydrolyzes chylomicron triglyceride. The product of this lipolytic process is the chylomicron remnant, which has only about 25 of the original chylomicron triglyceride remaining. Importantly, the chylomicron remnants are relatively enriched in...

Losing control of glucose

Fatigue Without sufficient insulin, or with ineffective insulin, glucose can't enter cells (such as muscle and fat cells) that depend on insulin to act as a key. (The most important exception here is the brain, which does not need insulin.) As a result, glucose can't be used as a fuel to move muscles or to facilitate the many other chemical reactions that have to take place to produce energy. A person with diabetes often complains of fatigue and feels much stronger after treatment allows glucose to enter his or her cells again.

Nutritional Considerations

A high susceptibility to obesity may also be the result of unlimited availability of palatable and high-calorie-density foods. Laboratory adult rats fed a ''supermarket diet'' consisting of high-carbohydrate high-fat foods (i.e., chocolate chip cookies, marshmallows, peanut butter, etc.), gained 2.5 times more weight than normal controls (402). In some animals, the weight gain was not reversed after the rat was switched back to chow. It is believed that supermarket diets increase the number and size of fat cells. In children the portion size offered and the type of food given also play a role. Repeated exposure to a larger portion size of macaroni and cheese resulted in 25 more calorie intake when compared with feedings of an age-appropriate serving size, particularly in older children (403). Therefore, while younger children may be better at regulating the amount of food consumed they may lose this ability as they grow older if exposed to large portion sizes (404).

Studies In Man Therapies

In type 2 diabetes some studies suggest that intensified glycemic control may improve cognition (96-99 but see ref. 100). However, the methodological quality of the studies is insufficient to draw firm conclusions (101). Alternative treatment modalities are also being considered. There is some evidence that treatment with the lipid-lowering drug atorvastatin has beneficial effects on learning in type 2 diabetes (102). Moreover, a recent randomized, double-blind, placebo-controlled crossover study showed that administration of the lip-hydroxysteroid dehydrogenase inhibitor carbenoxolone improved verbal memory after 6 weeks in 12 patients with type 2 diabetes (103). The rationale behind this treatment was that the compound might protect hippocampal cells from glucocorticoid-mediated damage that occurs in association with ageing (103).

Adiposetissue derived factors

Adipose tissue produces a large number of cytokines (Table 4.1) which include leptin, the product of the ob gene (Zhang et al., 1994), TNF-a (Hotamisligil et al., 1993a Kern et al., 1995), resistin (Holcomb et al., 2000 Steppan et al., 2001a, b McTernan et al., 2002a), adiponectin (Maeda et al., 1996 Hotta et al., 2000) and interleukin-6 (IL-6) (Mora and Pessin, 2002 Spranger et al., 2003), which may serve as important factors determining the pathogenesis of type 2 diabetes from obesity. This present chapter will discuss the regulatory effects of leptin, TNF-a, resistin, adiponectin, and IL-6 in the pathogenesis of obesity-related type 2 diabetes.

Pathophysiology of Adipose Tissues Obesity and Insulin Resistance

Lipid storage in adipose tissue represents excess energy consumption relative to energy expenditure, which in its pathological form has been coined 'obesity'. In recent years, overnutrition has reached epidemic proportions in developed as well as developing countries. This reflects recent lifestyle changes, however there is also a strong genetic component as well. While the biochemical mechanism(s) for this genetic predisposition are still under investigation, the genes that control appetite and regulate energy homeostasis are now better known. For example, adipocytes produce leptin (see above) that suppresses appetite and was initially considered a promising target for drug therapy. However, most overweight individuals overproduce leptin, and no more than 2-4 of the overweight population has defects in the leptin appetite One striking clinical feature of overweight individuals is a marked elevation of serum NEFAs, cholesterol, and triacylglycerols irrespective of the dietary intake...

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).

Antipsychotic Agents Psychiatric Drugs

Leptin The hormone leptin synthesized by adipocytes plays a key role in the regulation of appetite, food intake and body weight by acting in the hypothalamus at leptin receptors. In olanzapine-and clozapine-treated patients, serum leptin levels increase more rapidly than with other AAP drugs. This rapid increase in leptin levels may be a potential mechanism of causing insulin resistance (136-139).

Interventions to reduce maternal inflammation and insulin resistance

Physical activity is an effective intervention for reducing the risk of type 2 diabetes and associated metabolic anomalies such as insulin resistance, oxidative stress, and dyslipidemia.34 Physical activity activates the AMP-activated protein kinase (AMPK) enzyme, which increases glucose transport into the muscle, enhances fat oxidation, and reduces insulin resistance.7. Exercise, even intermittently, reduces the risk of GDM among obese women with BMIs > 33 by nearly two-fold.35 Women who exercise throughout pregnancy (i.e., perform endurance exercises > 4 times week) gain significantly less fat and had significantly lower increases in TNF-a and leptin during gestation.36 The changes in leptin, but not TNF-a, were correlated with reduced fat mass in physically active women. Possibly, the differences in TNF-a levels reflect the exercise-induced reductions in insulin resistance whereas the leptin changes are more closely linked to fat accretion. Nevertheless, moderate physical...

Glucose Transporters as Components of the Glucose Sensing Machinery

Specialized glucose-sensing neurons has been known for many years. As brain glucose levels rise, glucose-responsive (GR) neurons increase and glucose-sensitive (GS) neurons decrease their firing rate. Little is known about the mechanism by which GS neurons sense glucose. GR neurons appear to function much like the pancreatic p-cell with glucokinase modulating the KATP channel, leading to membrane depolarization, calcium influx and increased cell firing. In addition, in neurons and astrocytes the AMP-activated protein kinase (AMPK) acts as an energy sensor 40 . When glucose concentrations decline, AMP levels rise and activate AMPK, which alters neuronal activity. Many glucose-sensing neurons also respond to and integrate signals from other metabolites (e.g. fatty acids) and hormones such as leptin and insulin 39, 41, 42 . Deletion of a2-subunit of AMPK in both POMC and NPY AgRP neurons disrupted response to changes in glucose concentration in both neurons. Mice lacking AMPK activity in...

Erik J Henriksen contents

Insulin-resistant conditions such as pre-diabetes and type 2 diabetes are characterized by defects in the ability of insulin to activate glucose transport in skeletal muscle. One animal model that has proven useful in elucidating the multifactorial etiology of skeletal muscle insulin resistance is the obese Zucker (fa fa) rat, characterized by complete leptin resistance, massive central obesity, hyperinsulinemia, dyslipidemia, and oxidative stress (the imbalance between exposure of tissue to an oxidant stress and cellular antioxidant defenses). Studies published by our research group addressed the utility of two nutriceu-tical compounds, conjugated linoleic acid (CLA) and alpha-lipoic acid (ALA), both of which possess antioxidant properties, in improving the metabolic

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).

Pathogenesis And Pathophysiology

Hepatic lipid accumulation does not universally result in hepatocellular injury, indicating that additional secondary insults are important (19). Insulin resistance and associated metabolic disturbances in adipose-derived factors including FFA, tumor necrosis factor-a (TNF-a), leptin and adiponectin have been implicated in contributing to liver damage in NAFLD. Hyperinsulinemia and hyperglycemia may directly stimulate fibrosis by up-regulation of fibrogenic growth factor produced by hepatic stellate cells (20,21). Increased hepatic FFA oxidation can generate oxygen radicals with subsequent lipid peroxidation, cytokine induction and mitochondrial dysfunction (22). FFA may also lead to hepatocyte apoptosis, which is a prominent mechanism of cellular injury among NAFLD patients (23). Genetic polymorphisms of inflammatory and fibrogenic cytokines such as TNF-a, tumor growth factor-p, angiotensinogen have been implicated to influence progression to NASH, as has polymorphisms of manganese...

Physiology of Adipose Tissues

Among the endocrine factors, adipocyte-derived proteins with antidiabetic action include leptin, adiponectin, omentin and visfatin. For instance, in addition to its well-characterized role in energy balance, leptin reverses hyperglycemia by improving insulin sensitivity in muscles and the liver. According to the current view that intra-cellular lipids may contribute to insulin resistance, this occurs most likely by reducing intracellular lipid levels through a combination of direct activation of AMP-activated protein kinase (AMPK) and indirect actions mediated through central neural pathways 2 . Other factors tend to raise blood glucose, including resistin, tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4). TNF-a is produced in macrophages and reduces insulin action 3 . IL-6 is produced by

Jong Min Park and AnSik Chung

Obesity is rapidly increasing throughout the world, substantially shortening life expectancy, and closely correlated with the prevalence of diabetes and cardiovascular diseases. Plasma levels of leptin, tumor necrosis factor (TNF)-a and non-esterified fatty acids are elevated in obesity and substantially contribute to the development of insulin resistance.1 Although obesity research including studies of leptin2 and the leptin receptor gene3 has been extensively pursued for more than two decades, the molecular mechanisms of obesity are not yet completely understood. Finding target molecules of weight regulatory mechanisms will contribute to the development of safe and effective pharmaceuticals for blocking obesity and preventing diabetes and cardiovascular diseases. a-lipoic acid (LA) and its reduced dihydrolipoic acid (DHLA) are considered antioxidants (Figure 18.1). LA has components of a-keto dehydrogenases including pyruvate dehydrogenases that catalyze various redox-based...

Impact of antidiabetic therapies on coronary intervention

A smaller study of 54 patients who were randomised to pioglitazone or placebo has shown similar results, with less late luminal loss and in-stent restenosis in the pioglitazone group (Nishio etal., 2006). Leptin concentrations independently correlated with the late luminal loss on multiple regression analysis.

Transforming Growth Factor And Other Cytokines In Experimental And Human Diabetic Nephropathy

Genetic, hemodynamic, and metabolic factors are important in the pathogenesis of diabetic nephropathy. This chapter, complementing the coverage of related chapters in this book, will focus on some of the metabolic mediators, especially the various cytokines and growth factors, with particular focus on the transforming growth factor- (TGF-P) system. Various mediator factors and signal transduction pathways interact in an intricate circuitry of autocrine, paracrine, or even endocrine mechanisms when the kidney is chronically exposed to high ambient glucose concentrations. The effects of high glucose on renal cells may arise as a consequence of increased flux of glucose metabolism through the polyol pathway 1 , increased de novo synthesis of diacylglycerol (DAG) with subsequent activation of protein kinase C (PKC) 2, 3 , activation of the hexosamine pathway 4 , and increased non-enzymatic glycation of proteins 5, 6 . Recent studies have demonstrated the importance of many soluble...

Summary and conclusions

In writing this chapter, we set out to illustrate some of the problems that have beset the study of obesity genetics, to evaluate some of the techniques currently available and to provide some examples of the progress made to date and future prospects for this rapidly moving field. In the past few years alone, fascinating and specific new lines of investigation have been suggested by unravelling the genetic and molecular basis of elements of the leptin pathway and of syndromic forms of obesity such as the BBS.

The Hexosamine Biosynthetic Pathway

Interest in the relationship among glucose metabolism, diabetes, and the HBP was initiated by the discovery of its potential role in the pathogenesis of insulin resistance (12,13). Although high glucose, free fatty acids, and glucosamine (Glc) can all induce insulin resistance, several studies have suggested that the HBP contributes in each case (12-15). Furthermore, it has recently been proposed that the HBP functions in adipocytes, muscle cells, and pancreatic P-cells, as a nutrient-sensing pathway mediating responses to nutrient availability. For example, the adipocyte-derived hormone leptin is synthesized and secreted in response to increased HBP flux (16). Because it is beyond the scope of this chapter to review this aspect of HBP function, the reader is referred to refs. 12-16.

Pathogenesis of TD Genetic Factors

Many genes interact with the environment to produce obesity and or T2D. In the case of obesity, the most frequent mutation is that in the melanocortin-4 receptor, which accounts for up to 4 of cases of severe obesity. Other rare causes include mutations in leptin and the leptin receptor, prohormone convertase 1 (PC1) and pro-opiome-lanocortin (POMC). The gene variant most commonly associated with insulin sensitivity is the P12A polymorphism in PPARg, which is associated with an increased risk of developing T2D 15, 51 . A number of genes associated with P-cell dysfunction have been identified, including two non-coding single-nucleotide polymorphisms in transcription factor 7-like 2 (TCF7L2) and mutations in the mitochondrial genome that are also associated with neurosensory hearing loss 51 . Work is ongoing on many candidate genes, including calpain 10, adiponectin, PPAR-7 coactivator 1 (PGC1) and the glucose transporter GLUT2 51 .

Inflammation A Process Associated with Obesity Induced Insulin Resistance

Adipose tissue modulates metabolism by releasing NEFAs and glycerol, hormones -including leptin and adiponectin - and proinflammatory cytokines 19 . There is now clear evidence that obesity associated with or without T2D is an inflammatory state, consistent with the production of TNF-a and other cytokines by adipose tissue. Chronic inflammation of white adipose tissue characterized by macrophage infiltration is thought to contribute to insulin resistance associated with obesity, and in obesity, the production of many of these adipokines is increased. RBP4 induces insulin resistance through reduced phosphatidylinositol-3-OH kinase (PI3K) signaling in muscle and enhanced expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase in the liver through a retinol-dependent mechanism. By contrast,

Chronic Heart Failure and Abnormalities of Insulin and Glucose Metabolism

Insulin resistance, in the absence of diabetes, is a prognostic indicator in CHF secondary to valvular heart disease (Paolisso etal., 1999). Data are not available for CHF secondary to other aetiologies. Why insulin resistance is prevalent in patients with CHF is not fully understood, but the relationship is likely to be multifactorial (Coats and Anker, 2000). Hypotheses have arisen primarily from non-CHF populations. Possible contributing factors are sympathetic overactivity (Scherrer and Sartori, 1997), sedentary lifestyle, endothelial dysfunction, loss of skeletal muscle mass (Mancini etal., 1992) and influence of cytokines such as TNF-a (Levine etal., 1990 Miles etal., 1997) and leptin (Doehner etal., 2002) on peripheral insulin sensitivity.

The Association Between Obesity And Type Diabetes

Several mechanisms have been proposed to explain how excessive body weight is associated with Type 2 diabetes. In general, the accumulation of fat mass is associated with a decline in whole body insulin sensitivity. The distribution of obesity is important, with resistance to the action of insulin and glucose intolerance most closely associated with excess abdominal adipose tissue. As visceral adipose tissue increases plasma triglyceride (TG) concentrations are elevated, high-density lipoprotein (HDL) cholesterol decreases and low-density lipoprotein (LDL) cholesterol increases with a greater proportion of the more atherogenic small dense LDL particles (LDL subclass III). Other associated characteristics include an elevated plasma non-esterified fatty acid (NEFA) concentration, an increased plasminogen activator inhibitor 1 (PAI-1) concentration, hyperuricaemia and hypertension. Abdominal obesity is also associated with specific changes in skeletal muscle morphology, namely a...

Recent Developments

Endogenous and exogenous cannabinoids have been shown, in a large number of studies, to stimulate appetite. This effect is mediated through the CB1 receptor in the brain, and is involved in mediating the central effects of appetite-modulating peptides such as leptin. Pharmacological CB1 receptor blockade decreases appetite, and increases adiponectin expression and peripheral thermogenesis through effects at receptors on adipocytes and skeletal muscle, respectively. The recently published RIO (Rimonabant In Obesity)-Europe trial5 was a multicentre, randomized controlled trial of the CB1 antagonist rimonabant in over 1500 subjects who were either overweight or obese and had a high prevalence of dyslipidaemia or hypertension. In association with a hypocaloric diet, subjects taking 20 mg of rimonabant once daily lost a mean of 6.6 kg over a year. Weight loss was accompanied by improved insulin sensitivity and decreased waist circumference.

Agerelated Changes In Glucose Metabolism

There is substantial evidence that age-related impairment in both insulin action and beta cell function are key factors in the high incidence of diabetes in the elderly (6,7). Typical changes in body composition, including an increase in overall adiposity, but especially visceral adipose tissue appear to be the major factors responsible for the resistance to insulin action (8). This effect is, at least in part, mediated by alterations in fat-derived peptides (adiponectin, TNF-alpha, leptin) and increased circulating free fatty acid levels (9). Reduction in skeletal muscle mass (sarcopenia) and infiltration of muscle tissue by fat may also contribute to impaired insulin-mediated glucose disposal (10). Defective inhibition of hepatic glucose production by insulin is an additional contributor to glucose intolerance with aging (11).

Diabetes and Insulin Resistance

The majority of data for animal studies thus far suggest that adiponectin acts as an insulin-sensitizing hormone. Adiponectin-knockout mice develop insulin resistance either independently of diet or only after high-fat and high-sucrose diet, and treating these mice with adiponectin ameliorates their insulin resistance (35,42). The insulin resistance in adiponectin-deficient lipoatrophic and obese mice can partially be reversed via adiponectin administration and fully restored with both leptin and adiponectin supplementation (29). Furthermore, in a longitudinal study analyzing the progression of type 2 diabetes in obese monkeys, decrease in adiponectin closely parallels the observed reduction in insulin sensitivity, and the obese monkeys with greater plasma levels of adiponectin had less severe insulin resistance (43).

Adipokines Adiponectin

There is considerable interest in the relationship between the adipocyte-derived protein adiponectin in both type 2 diabetes and CHD. Adiponectin is a 244-amino-acid protein that, despite being solely derived from adipose tissue, is paradoxically reduced in obesity (Greenberg and Obin, 2006). Circulating adiponectin levels, ranging from 0.5 to 30 g ml in humans, are reportedly around 1000-fold higher than circulating levels of other hormones such as insulin and leptin. Prospective epidemiological studies have consistently demonstrated that decreased adiponectin concentrations are associated

Maternal inflammation insulin resistance and fetal growth

Is this rise in birth weight linked to an increased maternal subclinical inflammation and insulin resistance associated with obesity Preliminary data suggest that it may be.28 For example, Radaelli and co-workers29 measured circulating maternal and fetal cytokines and growth factors in three mother-infant cohorts divided into tertiles according to neonatal body fat. The only fetal factor associated with neonatal body fat was leptin (p < 0.006), whereas the only maternal factor associated with neonatal body fat was IL-6 (p < 0.01). None of the other inflammatory cytokines was elevated in the mothers at delivery. Possibly, the placenta releases some of the mediators of inflammation such as IL-6 into maternal circulation, which in turn blunts maternal insulin action and enhances the fetal fuel supply.

Other Metabolic Risk Factors

Elevated serum leptin levels is another factor that lately has been shown to be associated with insulin resitance (Liuzzi et al 1999). Hyperleptinemia was shown to be a strong predictor of first-ever acute myocardial infarction in obese individuals (Soderberg etal 1999).

Insulin Effects In The Central Nervous System

Given that insulin negatively regulates appetite in the CNS, the impact of CNS insulin on body weight regulation still remains widely unclear. In normal weight male subjects, insulin given intranasally over 8 weeks resulted in a weight loss of 1.3 kg and in a loss of 1.4 kg of body fat as determined by standard body impedance technique. Waist circumference decreased by 1.6 cm and plasma leptin levels dropped by an average of 27 . However, in normal weight female subjects, the same intervention yielded an increase of body weight by 1 kg mainly due to increased extracellular water (51).

Weight reduction by lifestyle modification

Lifestyle modification program for obese PCOS women was performed in one recent study and included a diet and exercise programme for 6 months. Obese women with PCOS were classified as responders to the intervention if they regained ovulation during the study. As a result of intervention, responders showed 11 per cent reduction in central fat, 71 per cent improvement in insulin sensitivity index, a 33 per cent fall in fasting insulin levels, and a 39 per cent reduction in LH levels, but none of these parameters changed significantly in obese PCOS who failed to restore ovulation pattern (Huber-Buchholz et al., 1999). An interventional study of 12 weeks of energy restriction and followed by 4 weeks of weight maintenance prescribing high protein or low protein diets for obese PCOS women was performed by Moran et al. (2003). They reported that pregnancies, improvements in menstrual cyclicity, lipid profile, and insulin resistance as well as decrease in weight (7.5 per cent) and abdominal...

Evidence For Role Of Tgfp In Diabetic Nephropathy

If TGF-P contributes to DN, the increase in renal TGF-P should be attributable to the diabetic state. High glucose, elevated angiotensin II, amadori-modified proteins, advanced glycation endproducts, thromboxane, endothelin, platelet-derived growth factor, and leptin have all been shown to stimulate TGF-P production by cultured renal cells, which include mesangial, proximal tubular, interstitial fibroblast, and glomerular endothelial cells (14-22). In humans with type 2 diabetes, the degree of glycemic control correlates with the increase in glomerular expression of TGF-P1 (2). Even in the absence of diabetes, TGF-P can reproduce the deleterious effects of diabetic metabolic features on kidney cells. For example, high glucose causes mesangial cell (MC) hypertrophy (23,24) and stimulates collagen I and IV expression (14). In normal glucose media, exoge-nously added TGF-P1 also promotes MC hypertrophy and ECM production (14,23). For interstitial fibroblasts in culture, high glucose...

Type Diabetesa Matter of Cell Life and Death

A variety of cytokines play a role in the pathogenesis of type 2 diabetes. The discovery that there is local induction of IL-1p production within islets in response to chronic glucose implies that IL-1 p plays a role in inducing p-cell apop-tosis in type 2 diabetes (42), as well as in type 1 diabetes (27, 50). In obesity-linked diabetes, certain adipocyte-derived cytokines are elevated in the circulation, including leptin, tumor necrosis factor a (TNFa), and IL-6. Intriguingly, leptin has recently been shown to modulate IL-1p-induced apop-tosis in human p cells (51). Some of these cytokines can induce p-cell apoptosis through induction of signaling pathways that activate the transcription factor NFkB (27). However, they may also activate signaling pathways that trigger increased degradation of IRS-2. Certain cytokines, such as leptin, IL-6, and IFN-g activate the Janus Kinase-2 Signal Transducer and Activator of Transcription (JAK STAT) postreceptor signaling pathway. This leads to...

Breast Cancer Risk and Diabetes Mellitus Type

The adipocytes, forming the belly fat, are now in the focus of metabolic research in oncology. Adipocytes produce adipocytokines, which are biologically active polypep-tides and act by endocrine, paracrine, and autocrine mechanisms most have been associated with MeS. Six adipocytokines - vascular endothelial growth factor, hepa-tocyte growth factor, leptin, tumor necrosis factor-a, heparin-binding epidermal growth factor-like growth factor, and interleukin-6 - promote angiogenesis. Obesity and insulin resistance, again, have been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis 12 . However, the picture is not as clear as to be expected because a case-control study in Chile did not show any association between obesity and breast cancer at any age, although the same study revealed that insulin resistance was independently associated with breast cancer in postmenopausal women, but not in premenopausal women 13 .

Population lessons from the pcos paradigm

In men, there are studies showing that after adjusting for measurement of obesity, fat distribution, and insulin resistance, the correlations of major cardiovascular risk factors with testosterone, but not with visceral fat or insulin, lost their statistical significance (25, 139). Other studies, however, found that, after adjustment for BMI and WHR, the negative correlation of testosterone with insulin and lipid levels remained statistically significant (140). Intriguingly, low testosterone levels in men may therefore be a component of the metabolic syndrome (141). This can also be suspected based on indirect evidence. Hypogonadal men are characterized by enlarged abnormal fat depots and some degree of insulin insensitivity, which is partly dependent on the degree of body fat excess (142). In contrast, suppression of testosterone secretion by long-term administration of a gonadotropin-releasing hormone analog has been found to increase serum leptin and insulin, which are markers of...

Effects of Estrogen on Hemostatic Factors

On the other hand, reduced fibrinolytic activity is associated with atherosclerosis and has been attributed to increased levels of the antifibrinolytic factor plasminogen activator inhibitor-1 (PAI-1) (53). Increased PAI-1 levels have been found in postmenopausal women, and a close relationship between low fibrinolytic activity, high PAI-1 and hyperinsulinemia has been observed in various populations (54). Even small doses of oral ERT activate the fibrinolytic system via a marked reduction in PAI-1 levels, with the greatest reduction occurring in women with the highest PAI-1 levels. Combination with progestogen does not appear to diminish this beneficial effect. In contrast to oral therapy, transdermal therapy does not seem to change PAI-1 levels (55,56). The activation of the fibrinolytic system by estrogens appears not to be dose-related, unlike the coagulatory activity that appears to be dose-dependent (53). On balance, therefore, HRT at low dosages may affect fibrinolytic activity...

Exogenous Sources of Advanced Glycoxidation End Products

Animal studies have demonstrated the close relationship between increased dietary AGE intake and development and or progression of many diabetes-related complications. Nephropathy, postinjury restenosis, accelerated atherosclerosis, and delayed wound healing were significantly inhibited by lowering dietary AGE intake (27-30). Sebekova and associates demonstrated in the remnant-kidney rat model that feeding an AGE-rich diet for 6 weeks increases kidney weight and causes proteinuria, independent of changes in glomerular filtration rate, pointing to the detrimental effect of such diet on the kidney (31). Of particular interest are studies showing that a low-glycotoxin environment can prevent or delay significantly autoimmune diabetes in successive generations of nonobese diabetic (NOD) mice (32) and to improve the insulin-resistant state in db db (+ +) mice (33). Reduction in exposure to exogenous AGEs of db db (+ +) mice, lacking in leptin receptor and thus prone to insulin resistance...

Diabetogenic Pregnancy Hormones

The natural tendency of normal pregnancy hormones is to sustain elevated postprandial blood glucose levels to provide nourishment to the fetus. Table 3 outlines the sequential rise of these hormones. The first of these hormones, human chorionic gonadotropin (hCG), does not, itself, possess diabetogenic properties. It does, however, maintain the corpus luteum, which produces progesterone, a hormone with powerful anti-insulin properties. Estradiol has weaker diabetogenic traits. Its full effect is difficult to determine because it is released almost simultaneously with the very potent progesterone. The major diabetogenic hormones of the placenta are hCS, previously referred to as human placental lactogen (hPL), and progesterone. Also, serum maternal cortisol levels (both bound and free) are increased. At the elevated levels seen during gestation, prolactin also has a diabetogenic effect (36).

Magnetic Resonance Imaging MRI and spectroscopy

Mri Spectroscopy Show Muscle

Figure 13.3 Assessment of Abdominal Fat Storage by Computed Tomography (CT) Representative cross-sectional abdominal CT scans of a lean (A) and an obese (B) research volunteer, demonstrating the fat muscle CT contrast shown with demarcations of visceral (large arrowheads), deep subcutaneous (open arrows) and superficial subcutaneous (closed arrows) adipose tissue (AT) depots. The fascia (small arrowhead) within subcutaneous abdominal AT was used to distinguish superficial from deep depot. In the two CT scans shown, the area of superficial subcutaneous AT was similar (144 vs 141 cm2), whereas areas of deep subcutaneous (126 vs 273 cm2) and visceral (84 vs 153 cm2) AT were quite different. Insulin-stimulated glucose metabolism was 6.1 and 4.0 mg min-1 kg FFM-1 in lean and obese volunteers, respectively (FFM fat-free mass). Reproduced from Kelley D E et al. (2000) Am J Physiol Endocrinol Metab 278 (5) E941-E948. Courtesy of the American Physiological Society. Figure 13.3 Assessment of...

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