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...

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.

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

Obesity Rats Pomc

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...

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).

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.

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.

Etiology And Precipitating Factors

Glucose levels rise in the setting of relative insulin deficiency. The low levels of circulating insulin prevent lipolysis, ketogenesis, and ketoacidosis (62) but are unable to suppress hyperglycemia, glucosuria, and water losses. Levels of counter-regulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone are elevated, increasing gluconeogenic substrates, gluconeogenesis, and glycogenolysis. Meanwhile, glucose utilization is decreased. Glucose levels rise, leading to glucosuria, osmotic diuresis, and dehydration (14). Those patients who are unable to maintain an adequate fluid intake to compensate for the urinary losses, for example, elderly patients, will develop marked hyperglycemia and a hyperosmolar state. Mental status changes are more common in HHS than in DKA because of the greater degrees of hyperosmolarity in HHS (63).

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

Pathogenesis and Pathophysiology

Growth hormone and Cortisol, all of which have well-described metabolic actions. The metabolic actions of cytokines are in general not so well understood and it is possible that many of these actions are mediated by hypothalamo-pituitary activation and subsequent elevation of catabolic hormones.

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...

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 activity...

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.

The Inflammation Syndrome Connection

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 cytokines.

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

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...

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

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

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).

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...

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...

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...

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).

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.

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...

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).

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

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...

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...

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).

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...

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 .

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...

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,

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...

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 .

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...

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...

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...

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).

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.

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...

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...

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

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...

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.

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.

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).

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).

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

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

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...

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