Lose Weight By Controlling The Fat Storage Hormone

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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...


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,...


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...

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

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.

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...

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.

The Inflammation Syndrome Connection

Allergic reactions may be greatest in one part of the body, such as in the gut or nasal area, but activated immune cells migrate throughout the body and frequently attack healthy cells, causing a wide variety of symptoms. In a sense, an allergic reaction shifts the normal biochemistry to a status resembling a military yellow or red alert. Such a heightened state boosts levels of other substances, such as adrenaline and the stress hormone cortisol. All of these stressful changes take a toll on the body and help deplete nutrients, so it is wise to reduce the symptoms of food allergies to relieve immediate discomfort and to lessen long-term wear and tear.

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...


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...

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.

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.

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...

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...

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...

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.

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.

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.

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).

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.

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).

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

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.

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.

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).

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...

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...

Diabetes Mcq Hyperglycemia

Davis SN, Shavers C, Costa F, Mosqueda-Garcia R (1996). Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. Journal of Clinical Investigation 98 680-91. Davis SN, Shavers C, Davis B, Costa F (1997). Prevention of an increase in plasma cortisol during hypoglycemia preserves subsequent counterregulatory responses. Journal of Clinical Investigation 100 429-38. Raju B, McGregor VP, Cryer PE (2003). Cortisol elevations comparable to those that occur during hypoglycemia do not cause hypoglycemia-associated autonomic failure. Diabetes 52 2083-89.

Diabetes Obesity and the Brain

Hypothalamus Energy Homeostasis Mc4r

Evidence now indicates that the brain processes information from adiposity signals such as the hormones insulin and leptin, which circulate in proportion to body fat mass, and integrates this input with signals from nutrients such as free fatty acids (FFAs). In response, feeding behavior, auto-nomic outflow, and substrate metabolism are adjusted in ways that promote homeosta-sis of both energy stores and fuel metabolism. The overarching hypothesis is that in times of plenty (ample fat stores and food availability), input to key brain areas from these afferent signals leads to inhibition of both energy intake and endogenous glucose production, while simultaneously increasing energy expenditure and mobilizing fat stores (Fig. 1) (2, 3). The net effect is that when the brain senses that body energy content and nutrient availability are sufficient, further increases of stored energy (in the form of fat) and circulating nutrients (such as glucose) are resisted. Conversely, a decrease in...

Hypoglycemia Unawareness

The mechanisms whereby hypoglycemia begets subsequent hypoglycemia unre-sponsiveness are not clear. The cortisol responses to the initial hypoglycemia have been implicated (81) and there are suggestions that changes in brain glucose metabolism may occur in response to hypoglycemia exposure (82).

Genetic Factors in Type Diabetes The End of the Beginning

The power of modern murine genetics means that naturally occurring or induced mutations resulting in a relevant phenotype can be po-sitionally identified and, in addition, targeted mutagenesis can reveal the potential contribution of any gene to glucose homeostasis. The importance of murine genetics has been emphatically shown in the field of energy balance and obesity, a topic of great importance to type 2 diabetes given that most type 2 diabetic humans are obese. The discovery of the leptin and melanocortin pathways controlling energy balance have largely been driven by murine genetics (10). The relevance of these pathways to the control of energy balance in humans has been repeatedly demonstrated, although there are some notable exceptions where humans and mice diverge (11).

Suketu Shah md Alina Gavrila md and Christos S Mantzoros md

Our understanding of the function of fat cells has changed dramatically with the realization of the endocrine function of adipose tissue. Initially thought to serve only as a repository for energy via storage of triglycerides, adipocytes are now known to secrete a variety of proteins with diverse metabolic functions. These proteins include leptin, TNF-a, plasminogen activator inhibitor-1, acylation-stimulating protein, resistin, and adiponectin (1,2). Adiponectin has received much attention for its putative role in diabetes and CVD. Besides being associated with the development of diabetes, it may also have a direct role in modulating inflammation and atherosclerosis and thereby be one of the factors that links obesity to CVD. Although its structure and source are known, the regulation of adiponectin remains to be determined. The various factors thought to be involved in controlling adiponectin production and secretion include obesity, nutritional status, hormones such as insulin,...

Physiological Response To Hypoglycemia

The physiologic counterregulatory response to hypoglycemia involves neuroendocrine, ANS, and metabolic processes. This includes the suppression of insulin release as well as secretion of glucagon and pancreatic polypeptide from the pancreas, epinephrine from the adrenal medullae, norepinephrine from sympathetic postganglionic nerve terminals and adrenal medulla, cortisol from the adrenal cortex, and growth hormone from the anterior pituitary gland (11-13). In humans, inhibition of insulin secretion is the initial defense against a falling glucose and occurs at a plasma glucose concentration of about 80 mg dL. The brain is one of the first organs affected and is most vulnerable to any glucose deprivation. Cortisol and growth hormone increase glucose production and restrain glucose disposal during hypoglycemia. However, these hormones have little or no role in the defense against acute hypoglycemia but become more important during prolonged hypoglycemia (9). Their effects do not become...

Counterregulatory Mechanisms

Because many physiological processes alter with advancing age in humans, it is important to determine whether the ageing process per se may affect the nature and efficacy of the glucose counter-regulatory response to hypoglycaemia. In non-diabetic elderly subjects, a study of the counter-regulatory hormonal responses to hypoglycaemia induced by an intravenous infusion of insulin suggested that diminished secretion of growth hormone and cortisol is a feature of advanced age (Marker, Cryer and Clutter 1992), and a modest impairment of hormonal counter-regulatory secretion was present with some attenuation of the blood glucose recovery (Marker et al 1992). Insulin clearance was reduced, as was the secretion of gluca-gon, while the release of adrenaline was delayed, and these changes were unaffected by preceding physical training, suggesting that they were not related to a sedentary lifestyle (Marker et al 1992). However, a study using the hyperinsulinaemic glucose clamp technique has...

Glucose Counterregulation

An increased frequency of severe or fatal hypoglycemia (Stepka, Rogala and Czyzyk 1993). A number of studies have evaluated glucose counter-regulation in elderly subjects to try to determine the cause of the increased frequency of hypoglycemia, and some important observations have emerged. Many elderly patients with diabetes have not been educated about the warning symptoms of hypoglycemia and as a consequence do not know how to interpret the symptoms when they occur (Thomson et al 1991). The most important hormone in the defence against hypoglycemia in normal subjects is glucagon. If glucagon responses are deficient, epinephrine becomes important, and growth hormone and cortisol come into pay if hypoglycemia is prolonged for several hours. Gluca-gon and growth hormone responses to hypoglycemia are impaired in healthy elderly subjects and to an even greater extent in older patients with diabetes (Figure 2.7) (Meneilly et al 1994). Even when they are educated about the symptoms of...

Homeostasis And Organ Crosstalk

However, there has been growing appreciation that adipose tissue is more than simply a fat storage and buffering compartment. It is an extremely active endocrine organ, playing an important role in signalling to muscle, liver, and central nervous system by secreting the so-called adipocytokines (leptin, resistin, adiponectin) and inflammatory mediators such as TNFa, IL-6, and PAI-1 (14). Rossetti and collaborators have shown through an elegant set of in vivo studies in rodents that a sustained elevation of plasma FFAs induces a rise in the LCFA-acylCoA pool within the hypothalamus, which acts as a signal for nutrient availability, and which is sufficient to inhibit both food intake and hepatic glucose production (15,16). Central administration of oleic acid is able to mimic the effects of plasma FFAs on feeding behavior, and pharmacological intervention aimed at reducing intracellular LCFA-acylCoA abundance, either by blunting their synthesis or by favoring their oxidation, induces a...

Extrapancreatic Effects Of Sulfonylureas And Meglitinides

Large randomized trials, such as the UKPDS, usually showed a weight gain of 2 to 4 kg with longer acting sulfonylureas, e.g., glibenclamide and chlorpropamide. This weight gain can be avoided by dietary advice if patients are compliant. Indeed, no weight gain was observed in smaller studies with glipizide, glimepride, and the shorter acting substances (20). Weight gain is apparently related to the increase in insulin and its antilipolytic and trophic action on fat cells, and is probably enhanced by the addition of further agents inhibiting lipolysis, such as beta-blockers or the thiazolidinediones, which promote fat cell differentiation and proliferation.

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)...

Tracers for the study of triglyceriderich lipoprotein kinetics Chylomicrons

The fate of dietary fatty acids can be traced by adding a radiolabeled triglyceride to a mixed meal and tracking the appearance of the labeled fatty acid in the plasma space and its subsequent uptake in regional fat depots (Roust & Jensen 1993 Romanski et al. 2000 Jensen et al. 2003). Triglycerides or fatty acids labeled with stable isotopes can be administered as part of a meal in order to generate labeled chylomicrons (Evans et al. 2002 Barrows et al. 2005). The technique can be extremely useful in assessing patterns of dietary fat storage. It has the advantage that the secreted chylomicrons contain physiological mixed triglycerides. A limitation is that tracer input (i.e. the rate of absorption of labeled chylomicrons) is unknown.

Oral diabetes medications or oral hyperglycemic medications

Stress hormones or counter-regulatory hormones Hormones released during stressful situations, such as an illness or infection. These hormones include glucagon, epinephrine (adrenaline), norepinephrine, cortisol, and growth hormone. They cause the liver to release glucose and the cells to release fatty acids for extra energy. If there's not enough insulin present in the body, these extra fuels can build up and lead to hyper-glycemia and ketoacidosis.

Antecedent Hypoglycemia And Hypoglycemiaassociated Autonomic Failure

Cryer earlier coined the term hypoglycemia-associated autonomic failure (HAAF) to describe the syndrome of acquired counterregulatory deficits associated with prior hypo-glycemia. This syndrome is experienced by individuals with T1DM and involves blunted neuroendocrine counterregulatory responses to hypoglycemia, lowered glycemic thresholds for activation of counterregulatory defenses, and HU. To test the hypothesis that hypo-glycemia itself causes reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia, Heller and Cryer measured counterregulatory responses during repeated hypoglycemic clamp studies (13). These experiments determined that two episodes of antecedent moderate hypoglycemia (50 mg dL) resulted in significant reductions of plasma epinephrine, glucagon, pancreatic polypeptide, and cortisol responses to next day hypo-glycemia. Neurogenic and neuroglycopenic symptom responses were also reduced after antecedent hypoglycemia (13). Importantly, Dagogo-Jack et...

Insulin Resistance and Its Relevance to Treatment

Catecholamines And Insulin Resistance

Insulin regulates several key metabolic steps (fig. 1). In doing so, insulin is opposed by the four counterregulatory hormones (the rapid-acting glucagon and catecholamines, and the slow-acting growth hormone and cortisol). Insulin affects the pathways of glucose utilization as well as the synthesis and degradation of macromolecules (glycogen, triglycerides and proteins) by regulating the activity of 'key enzymes'. Indeed, along each metabolic pathway, there is one or more key step(s) catalyzed by key enzymes. These are enzymes which, because of their low activity and sensitivity to regulatory factors (including hormones), regulate the overall rate of the pathway to which they belong. In particular, insulin (or, better, its prevalence over the counterregulatory hormones) exerts the following effects (fig. 1)

Pathophysiology Of Macrosomia

Pathophysiology Undernutrition

Maternal malnutrition was considered the cause of islet cell hypoplasia (34,35). Later study demonstrated that the glycemic response to insulin was also reduced in individuals who had been thin at birth (44). Large studies in Sweden and the US have confirmed the association of fetal undernutrition with later type 2 diabetes risk (36,37). The adult offspring of women who had starved during the last trimester of pregnancy during the Dutch famine at the end of World War II have also been found to have increased risk for IGT (38). Underweight for gestational age has been associated with increased cortisol axis activity in urbanized South African 20-year olds who were not obese. They also had IGT compared to normal birth weight controls (39).

What is the Pathophysiology of Elevated Plasma FFAs

Adipocyte Lipolysis And Circulatory Ffa

An important clue to the existence of other adipose tissue lipase enzymes came from studies of mice lacking HSL, because they have normal body weight and reduced, not increased, fat mass (49-51), and exhibit accumulation of diacylglycerol (DAG) in fat cells (52). In addition, HSL-deficient mice showed that HSL-independent lipolysis is increased upon fasting (53). These data suggested that at least one other unidentified lipase exists, which is presumably responsible for the hydrolysis of TG into DAG, the latter being the main substrate for HSL. Indeed, Zechner and collaborators recently discovered a new lipase that is highly expressed in adipose tissue, which they named adipose triglyceride lipase (ATGL) (54). ATGL initiates the hydrolysis of TG, generating DAGs and FAs. Lipases identified at more or less the same time by Villena et al., and Jenkins et al., called desnutrin and the calcium-dependent phospholipase iPLA2 respectively, were later found to be identical to ATGL (36,55)....

Maternal Endothelial Dysfunction

Endothelial Dysfunction Preeclampsia

Tissue factor, E-selectin, platelet-derived growth factor, endothelin (35), and vascular cell adhesion molecule-1 (VCAM-1) (36). There is evidence of increased oxidative stress (37), increased lipid peroxidation (38), and platelet activation (39), as well as early increases in leptin (40). Studies demonstrate decreased production of endothelial-derived vasodilators, such as nitric oxide (NO) and prostacylin, and increased production of vasoconstrictors, such as endothelins and thromboxanes (41-43). Maternal vascular reactivity to vasopressors including angiotensin II and norepinephrine is

Molecular Cell Biology Of Endothelial Dysfunction In Diabetes

High Glucose Insulin Pathway

Of atherothrombosis and microangiopathy. These effects may be mediated through the associations of obesity with hypertension, dyslipidaemia and insulin resistance, and also through mediators directly secreted by adipocytes, such as TNF-a, leptin and PAI-1. For example, obesity-associated proteinuria may be related to hyperfiltration, increased renal venous pressure, glomerular hypertrophy and increased matrix production through increased synthesis of vasoactive and fibrogenic mediators, such as angiotensin-II, insulin, leptin and TGF-p1 87 .

Fat Diversion from Adipose to Nonadipose Tissue and Lipotoxicity

It is noteworthy that adipose tissue-derived hormones may modulate hepatic TG content leptin overexpression decreases hepatic lipid content in lipodystrophic A-ZIP F-1 mice (134), as does adiponectin in liver and muscle of obese mice (135), both being accompanied by improved insulin sensitivity. Recently the adipocyte-derived hormone adiponectin has been shown to reverse insulin resistance associated with both lipoatrophy and obesity (135). Adiponectin reduced the triglyceride content of muscle and liver in obese mice by increasing the expression of fatty acid oxidation and energy dissipation in muscle. Unger has argued against the conventional view that the physiological role of leptin is to prevent obesity during overnutrition and proposed that the role of hyperleptinemia in conditions of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing upregulation of lipogenesis and by increasing fatty acid oxidation (136-138). Adenoviral-mediated expression...

Mechanisms Of Hyperfiltration In Diabetes

In addition to possible direct effects of diabetes on NOS activities, the NO-mediated alterations in renal hemodynamics may be related to increased activity of factors, which act as NO-dependent vasodilators or activate NO-cGMP pathway as a part of their signal transduction. De Vriese, et al 63 reported that neutralization of vascular endothelial growth factor (VEGF) with an antibody ameliorated diabetic hyperfiltration. VEGF has been implicated with non-hemodynamic pathways in the pathogenesis of diabetic complications, and also possesses vasomotor effects mediated by NO. Some other factors implicated in the pathophysiology of diabetic glomerulosclerosis, such as TGF-beta and leptin, also signal in part via NO. However, whether these pathways may have impact on glomerular hemodynamics remains to be elucidated.

Maternal obesity and inflammation

The increase in fat oxidation among the obese women was significantly correlated with serum leptin concentrations (r 0.76, p < 0.005).19,20 Longitudinal changes in insulin sensitivity were also compared among women with BMIs < 25, between 25 and 30, and > 30.21 Although 50 to 60 decreases in insulin sensitivity were noted in all groups from before conception through late pregnancy (p < 0.0001), the obese subjects were significantly less insulin-sensitive or more insulin-resistant than the lean women (p < 0.0001) and overweight women (p < 0.004), particularly prior to conception or at 12 to 14 weeks of gestation. Since these preliminary studies showed that insulin sensitivity was lower in obese than in non-obese pregnant women, we studied the relationship between BMI and maternal cytokine levels in 51 women at 28 weeks' gestation.24 At the beginning of the third trimester, the BMI values of these women averaged 32 9 kg m2 the range was 21 to 54 kg m2. BMI correlated with...

Clinical Health Care Concerns

While excess glucose stimulates fetal insulin production and results in increased fetal growth and adiposity, fetal growth appears to be increased even in well-controlled pregnancies complicated by diabetes. It is, therefore, possible that, in addition to hyperglycemia, alterations in other maternal fuels or derangement in placental transport and metabolism of fuels are involved in fetal overgrowth. There is evidence that increased amino acids and free fatty acids are present in mothers with diabetes. In addition, placental transport and metabolism of amino acids and free fatty acids appear to be altered in diabetic pregnancy, and there may also be upregulation of placental gene expression, resulting in increased leptin and inflammatory markers. In pregnancies complicated by type 1 diabetes, excess fetal growth is associated not only with increased placental transport of glucose and amino acids, but also with increased placental lipoprotein lipase.

The Somogyi Phenomenon The Concept Of Rebound Hyperglycaemia

Counterregulatory Hormones Diabetes

In the late 1930s, a Hungarian biochemist, Michael Somogyi, working in St Louis, USA, suggested that nocturnal hypoglycaemia might provoke rebound hyperglycaemia on the following morning, and he supported his hypothesis with a demonstration that reducing evening doses of insulin led to a reduction in fasting urinary glycosuria (Somogyi, 1959). He proposed that nocturnal hypoglycaemia provokes a counterregulatory response with rises in plasma epinephrine, cortisol and growth hormone resulting in the release of glucose from the liver and inhibition of the effects of insulin over the next few hours. The logical conclusion from his hypothesis was that this 'rebound' elevated fasting blood glucose in the morning should be treated, not by an increase in the evening dose of insulin, but paradoxically by a reduction. The idea of 'rebound hyperglycaemia' following nocturnal hypoglycaemia, (also known as the Somogyi phenomenon) as an explanation for a high fasting blood glucose in...

Obesity and inflammation

In addition to TNFa and IL-6, the major adipocyte cytokines, three other important proteins, leptin, adiponectin, and resistin, need mention. While leptin is known for its function as a satiety signal that inhibits feeding, it has additional roles as a regulator of sexual function and as an immune modulator. It is also proinflammatory and induces platelet aggregation.47-49 Thus, its elevated concentrations may contribute to the pro-inflammatory state of obesity and to atherogenesis in the long term. On the other hand, adiponectin, secreted in abundance by adipocytes in normal subjects, is anti-inflammatory and thus potentially anti-atherogenic. In contrast to leptin, its concentration falls with weight gain and in obesity.50,51 It has been suggested that a low adiponectin concentration may be a marker for atherosclerosis and coronary heart disease.52 Furthermore, in several experimental models, it has been shown to be protective to the arterial endothelium.

How Obesity Causes Diabetes Not a Tall Tale

Perhaps the best thrifty gene candidate is the gene that encodes leptin, a hormone produced by adipose tissue and the absence of which leads to obesity and insulin resistance in rodents and humans (13). Leptin functions physiologically as a signal of energy stores, inhibiting food intake and accelerating energy metabolism (13). 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...

Liver intrahepatic lipids

Pharmacological and lifestyle intervention studies successfully found the association between improved insulin sensitivity or splanchnic glucose uptake and decreased hepatocellular fat content in T2DM after glitazone treatment (Katoh et al. 2001 Carey et al. 2002 Mayerson et al. 2002 Bajaj et al. 2003), in lipodystrophic patients due to the leptin treatment

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...

Medical Complications

There is a large body of literature demonstrating that the lipotoxic fat is the visceral adipose tissue this may account for the differences in the prevalence of insulin resistance in obese individuals (52,53). Chen et al. suggested that this syndrome is characterized by the linking of a metabolic entity (hyperinsulinemia insulin resistance, hyperlipidemia, and obesity) to hemodynamic factors resulting in hypertension through a shared correlation with hyperinsulinemia insulin resistance (54). Low-grade systemic inflammation, elevated leptin concentration, and low adiponectin level are described in very young obese children, correlating with a range of variables of metabolic syndrome. Inflammation and adipocytokines can play an important role in the etiopathogeny of metabolic syndrome (55). However, parents of obese children and adolescents usually report that their children snore loudly and sometimes appear to stop breathing during sleep. The apnea may be obstructive, central, or...

Clinical Emergencies in Diabetes Diabetic Ketoacidosis and Hyperosmolar Nonketotic Syndrome

The hormonal pattern favoring DKA is represented by severe insulin deficiency and or excess of counterregulatory hormones (or stress hormones) which include glucagon, catecholamines, cortisol and GH. Among counterregulatory hormones, however, glucagon plays the major role, so that the key hormonal condition favoring DKA is depression of the insulin glucagon ratio. Insulin deficiency may occur because of interruption or inadequacy of insulin administration or in the setting of the first manifestation of type 1 diabetes. Counter-regulatory hormones may increase following physical (infections, surgery, trauma) or emotional stresses, and oppose insulin action. In addition, epineph-rine may also stimulate glucagon release, which is also favored by lack of insulin.

Pathological causes of obesity

Single gene defects, including leptin deficiency, leptin receptor deficiency, melanocortin-4 receptor deficiency and pro-opiomelanocortin deficiency, have been described in children but are extremely rare (Farooqi and O'Rahilly, 2000). These children develop severe early-onset obesity in the first 2 years of life. Although these conditions are rare they have enabled us to gain valuable insight in to the potential mechanisms involved in human weight control with potential implications for the development of effective pharmacological interventions in obesity management.

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,...

The Clinical And Molecular Phenotype Of Pcos

The fundamental manifestation of PCOS is excess in androgen secretion by the theca cells of the ovary and or the zona reticularis of the adrenal cortex (18). Theca cells obtained from women with PCOS have an inherent tendency to synthesize and secrete excessive amounts of androgen. This phe-notype persists despite many passages in cell culture, indicating that it is an intrinsic property of PCOS theca cells (19). A number of molecular studies suggest that increased functional activity of cytochrome P450 17-alpha hydroxylase (CYP17), cholesterol side chain cleavage P450 (CYP11A), and 3-beta hydroxysteroid dehydrogenase (HSD3B2) contribute to the molecular phenotype of PCOS theca cells (20). Furthermore, recent studies using DNA microarrays in cultured theca cells from women with PCOS reported increased expression of the genes encoding aldehyde dehydrogenase-6 and retinol dehydrogenase-2. These factors play a role in all-trans-retinoic acid synthesis and the transcription factor GATA6...

Gestational Hyperandrogenism of Maternal Origin

The origin of the androgen excess during pregnancy in women with PCOS women is uncertain but it could be due to increase in androgen production by the maternal theca interstitial cells stimulated by hCG. In this respect, the same investigators also reported that after delivery, androstenedione levels and ovarian volume of patients with PCOS were increased, suggesting that their ovaries were persistently stimulated during pregnancy (61). In addition, while the human placenta lacks 17b-hydroxylase and 17, 20-lyase, it does express 17 -hydroxysteroid dehydrogenase (17 b-HSD) and aromatase as well as 3b-hydroxysteroid dexydrogenase (3b-HSD) (62). It can therefore synthesize androstenedione from adrenal or ovarian DHEAS, and can continue with the synthesis of both testosterone and estradiol. These data support the concept that fetal growth restriction, an early marker of adult disease, is somehow related to prenatal exposure to excess androgens. Interestingly, a recent study suggested...

Dietary Modifications

Chronic consumption of high glycemic index foods, such as white bread and refined sugars, may also lead to chronically high oxidative stress and release of stress hormones (such as cortisol), which initiates the inflammatory signaling pathways. The consumption of high glycemic index foods results in higher and more rapid increases in blood glucose levels than the consumption of low glycemic index foods. Rapid increases in blood glucose are potent signals to the p-cells of the pancreas to increase insulin secretion. Over the next few hours after eating high glycemic foods, the high insulin levels induced by consumption of high glycemic index foods may lead to hypoglycemia. On the other hand, the consumption of low glycemic index foods results in lower but more sustained increases in blood glucose and lower insulin demands on pancreatic p-cells. The release of stress hormones, such as epinephrine and cortisol, are produced with dramatic increases and decreases in blood sugar levels....

Actions of Insulin and Glucagon

The cardinal hormonal alteration that triggers the metabolic decompensation of DKA is insulin deficiency accompanied by an excess of glucagon and the stress hormones epinephrine, norepinephrine, cortisol, and growth hormone (2,3,6). Insulin stimulates anabolic processes in liver, muscle, and adipose tissues and thereby permits glucose utilization and storage of the energy as glycogen, protein, and fat (see Table 1). Concurrent with these anabolic actions, insulin inhibits catabolic processes such as glycogenolysis, gluconeogenesis, proteolysis, lipolysis, and ketogenesis. Insulin deficiency curtails glucose utilization by insulin-sensitive tissues, disinhibits lipolysis in adipose tissue, and enhances protein breakdown in muscle. Glucagon acting unopposed by insulin causes increased glycogenolysis, gluconeogenesis, and ketogenesis. Although insulin and glucagon may be considered as the primary hormones responsible for the development of DKA, increased levels of the stress hormones...

Depression Treatment Considerations For Diabetic Patients

CRH antagonists CRH acts through CRH1 receptors to produce a number of anxiety- and depression-like symptoms, which have led to the consideration of CRH1 receptors as potential drug targets. Several small non-peptide molecules that are able to pass the blood-brain barrier have entered clinical development. One agent, NBI-30775 R121919, was reported to have a clinical profile comparable to paroxetine (87). This compound was administered to 24 patients with a major depressive episode primarily for a safety and tolerability study. The drug was found to be tolerated by patients and did not interfere with cortisol secretion at baseline or following an exogenous CRH challenge (88). Significant reductions in both patient- and clinician-rated depression and anxiety scores were found. Of interest is that mood symptoms worsened following drug discontinuation. CRH1 receptor antagonism for the treatment of depression has demonstrated potential therapeutic value and merits further examination....

The Role of Intensive Glycemic Control in the Management of Patients who have Acute Myocardial Infarction

It is not clear whether stress hyperglycemia predisposes one to a worse prognosis or is simply a marker for more extensive myocardial damage. Acute hyperglycemia in AMI probably is not related simply to stress-mediated release of coun-terregulatory hormones (catecholamines, gluca-gon, and cortisol) because glucose levels that are measured upon hospital admission do not

Hypoglycemia In The Nondiabetic State

Counterregulation The initial endocrine response to a fall in blood glucose in non-diabetic humans is the suppression of endogenous insulin secretion. This is followed by the secretion of the principal counterregu-latory hormones, glucagon and epinephrine (adrenaline) (5). Cortisol and growth hormone also contribute, but have greater importance in promoting recovery during exposure to prolonged hypoglycemia. These hormones are released through simultaneous activation of the hypothalamo-pituitary-adrenal axis and central autonomic centers within the brain, which stimulates the peripheral autonomic nervous system, particularly the sympathoadrenal system. Activation of the peripheral sympathetic nervous system and the adrenal glands provokes the release of a copious quantity of catecholamines, epinephrine, and norepinephrine, which have potent effects in mobilising 3-carbon precursors for glucose synthesis from peripheral tissues (skeletal muscle and adipose tissue) and also convert...

Risks of Insulin Therapy

The other major risk of insulin therapy is weight gain. Insulin promotes fat storage in adipocytes and protein synthesis in muscles. It participates in many other growth and anabolic pathways. In addition, patients who experience improved control with intensive therapy eliminate glucosuria, go into positive caloric balance, and provoke further weight gain. In the DCCT, patients treated with intensive insulin therapy had a substantially higher incidence of obesity than those given conventional therapy (36).

Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

The first part was shown to be true in the case of a three days (Bachmann et al. 2001) high fat diet and intravenous intralipid heparin infusion induced peripheral insulin resistance (Bachmann et al. 2001 Boden et al. 2001). Researchers could observe a parallel increase of IMCL content, relatively more pronounced in the tibialis anterior muscle of young healthy humans (Bachmann et al. 2001 Boden et al. 2001). Similar results, accompanied by molecular adaptations favouring fat storage in muscle, were found in another study after one week of high fat diet (Schrauwen-Hinderling et al. 2005). Inducing insulin resistance by i.v. amino acid infusion during euglycaemic-hyperinsulinaemia (Krebs et al. 2001) was met by a subtle increase of IMCL content in soleus muscle. IMCL content decreased with increasing insulin sensitivity due to 8-10 months of leptin replacement in patients generalised lipodystrophy (Simha et al. 2003) and 6 months of caloric restriction with or without exercise in an...

Classification of Diabetes Mellitus

The most common associations with insulin resistance are obesity and lack of physical fitness. A wide range of other conditions is associated with insulin resistance (see Table 1.2) and many also increase the risk of developing diabetes. In prospective studies, obesity is the strongest modifiable risk factor that predicts future risk of diabetes in nondiabetic populations.37 Body fat distribution is important also visceral (abdominal) obesity, as measured by the waist hip ratio, is a stronger predictor than body mass index.38 It is thought that the increased fat mass in obese individuals augments insulin resistance by a number of different mechanisms, including increased release of free fatty acids and a number of adipocytokines including tumor necrosis factor-a, leptin, resistin, and interleukin-6. Some workers have also proposed, in the lipotoxicity theory that obesity not only affects insulin sensitivity, but also pancreatic function, with excess fatty acids...

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.

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...

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...

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...

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...

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.

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.

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.

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.

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.

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

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...

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...

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.

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...

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...

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