Cure for Diabetes Found

Reverse Diabetes Now

Reverse Diabetes Now is created by Matt Traverso a well-known medical researcher and diabetes expert. In fact, the author has spent years researching and studying to create this revolutionary treatment for diabetes. This entire e-book contains 114 informative pages, covering a lot of useful knowledge and treating plan for diabetes that people should learn and follow. The whole guidebook is divided into 12 small sections. Firstly, people will get the overview of diabetes and how you can realize if you are suffering from this terrible disease. Reverse Diabetes Today PDF is an extremely comprehensive treatment that encourages people to make positive changes in daily habits, more concretely, dieting, regularly exercising, and weight managing routines to reverse diabetics. Read more here...

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Basic principles of the euglycaemic hyperinsulinaemic clamp technique

The hyperinsulinaemic euglycaemic clamp technique was developed by Andres etal. (1966) and further developed and widely studied by DeFronzo etal. (1979) (see also Sherwin etal. 1974 Insel etal. 1975). From a mechanistic point of view, this technique breaks the physiologically-operating feedback loop between blood glucose concentration and pancreatic insulin secretion and applies a negative feedback principle to the system regulating the blood glucose concentration (Bergman etal. 1985). In the postabsorptive state of nondiabetic individuals, the rate of endogenous glucose output originating from hepatic ( 95 ) and renal ( 5 ) glucose release exactly matches the rate of whole body glucose utilisation, resulting in constant glycaemia (Figure 4.3). The administration of exogenous insulin under these conditions reduces endogenous glucose output and increases whole body glucose utilisation, which both result in a decline of blood glucose concentration. This decline can be prevented when an...

Standardised indices of insulin sensitivity derived from the M value

For purposes of comparison, M values should be standardised (Ferrannini & Mari 1998). The steady state rate of whole body glucose metabolism is frequently normalised for bodyweight (Mbw), fat free mass (Mffm), rate of resting energy expenditure (Mree) and steady state plasma insulin concentration during the clamp (M I) (Bergman etal. 1985 Ferrannini & Mari 1998). Normalisation of the M value for the mean steady state concentration of plasma glucose yields the metabolic clearance rate of glucose (MCR) (Ferrannini & Mari 1998), which is able to account for small differences in glycaemia during a clamp. Any of these normalisations may be advantageous is some cases but bear pitfalls in others. Although several studies could demonstrate adipose tissue glucose uptake under insulin stimulated conditions in vivo (Bjorntorp etal. 1971 Virtanen etal. 2002), it is recommended that

Example of a protocol for insulin infusion

The following paragraph describes the preparation of an insulin infusate for a hyperinsuli-naemic (40 mU-m-2-min-1) euglycaemic clamp test. Table 4.3 provides an infusion scheme for the priming of the insulin space. The continuous infusion rate of the insulin infusion pump is chosen to be 20 ml per hour. 2 ml of blood are drawn from the participant and are promptly added to 48 ml of isotonic saline in a sterile syringe (50 ml). Then the required dose of human insulin is added, calculated as follows INSULIN (I U ) - Ins(40 mU m-2 min-1) BSA(m2) 60(min) Syringe Vol. (50 ml) (. .) Pump factor (20 ml h) 1000 INSULIN (I.U.) 6 BSA(m2) where Ins represents the rate of insulin infusion normalised to body surface area, BSA the body surface area (expressed in square metres), and the pump factor is the continuous infusion rate of the insulin infusion pump (ml h, here chosen to be 20 ml per hour). The number 1,000 in the denominator converts the insulin units from mU to I.U. If more than 50 ml of...

Reproducibility of insulin sensitivity obtained from clamp tests

Studies on the reproducibility have been performed under several metabolic conditions including lean and obese as well as glucose tolerant and intolerant individuals (DeFronzo etal. 1979 Del Prato etal. 1986 Morris etal. 1997 Bokemark etal. 2000 Soop etal. 2000). The conclusive finding of these studies is that the M value obtained from the hyperinsuli-naemic euglycaemic clamp test is a repeatable measure of insulin sensitivity. In these studies the time interval for the repetitive assessment of insulin sensitivity varied from two days to four weeks. The hyperinsulinaemic euglycaemic clamp technique was found to have a coefficient of repeatability of 0.85-1.0, which corresponds to an intraindividual coefficient of variation of 10 (Del Prato etal. 1986 Morris etal. 1997 Bokemark etal. 2000 Soop etal. 2000).

Stepped hyperinsulinaemic glucose clamp tests

In order to assess whole body glucose metabolism under conditions where more than one insulin dose is given during a single clamp experiment, a stepped hyperinsulinaemic glucose clamp test protocol can be applied (Basu etal. 2000 Bavenholm etal. 2001 Miyazaki etal. 2001 Anderwald etal. 2002). Because each step of hyperinsulinaemia needs at least 100 minutes to approximate steady state conditions, the total duration of the clamp experiment becomes a limiting factor. Two- or three-step hyperinsulinaemic glucose clamp tests are most commonly applied. In order to avoid carry over effects from the previous insulin infusion step, the experiments should be started with the lowest and end up with the highest insulin infusion rate. For example, the insulin infusion rates of a two-step hyperinsulinaemic glucose clamp test could be 40 mU-m-2-min-1 during the first and 160 mU-m-2-min-1 during the second step, whereby each step of the insulin infusion rate is maintained for at least 100 minutes....

CD36 SHR and Insulin Resistance

Until recently, evidence for an in vivo role for CD36 in FA metabolism was indirect and relied on the pattern of tissue distribution and on alterations in CD36 expression with metabolic or pathologic states. CD36 expression is increased, for example, in mice fed a high-fat diet and in animal models of genetic obesity and diabetes 47-52 . In 1999, Aitman et al. suggested, based on genetic linkage studies, that CD36 deficiency may underlie defects of FA metabolism and insulin responsiveness in the spontaneously hypertensive rat (SHR), which is a well-studied rodent model of human syndrome X 107 . Based on in vitro studies implicating CD36 in FA transport, it was proposed that the primary genetic defect in SHR might be compromised tissue FA utilization, which would contribute to the pathogenesis of insulin resistance by producing secondary alterations in basal glucose metabolism. An SHR congenic strain was generated by replacing a small region of chromosome 4 containing the deletion...

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...

Intravenous insulin infusion test

The intravenous insulin infusion test has been used as a tool for identifying type 1 diabetes patients who are at increased risk of hypoglycaemia during intensive therapy. The presence of neurological symptoms of hypoglycaemia or further decline of plasma glucose to below 1.9mmol l after intravenous insulin (40mu kg h) were considered a sign of an inadequate counterregulatory response and increased risk of severe hypoglycaemia was predicted on the subsequent application of intensified insulin therapy (White et al. 1983). A similar protocol was used by Ryder et al. to show that severe hypoglycaemia and counterregulatory failure were more common in people with a history of severe hypogly-caemia and that those with classical autonomic neuropathy did not correspond (Abramson et al. 1966). Bolli and colleagues further modified the insulin tolerance test by suggesting that the subcutaneous route more closely mimicked the clinical situation (Bolli et al. 1985). Overall, the insulin tolerance...

Onestep hyperinsulinaemic hypoglycaemia clamp

In a one-step study, the infusions of insulin and glucose are initiated as describe above to maintain euglycaemia for a period of stabilisation and then the glucose infusion is reduced or stopped, causing the plasma glucose to drop to the predetermined level within a fixed time (Maran et al. 1991). These can be quick fall or slow fall depending on the relative rates of insulin and glucose. The glucose infusion is then restarted to maintain the hypoglycaemia at a fixed plasma glucose level for a fixed period of time. At the end of the study the glucose infusion is increased and the insulin stopped to restore euglycaemia.

CD36 and Insulin Responsiveness in the Mouse

As already noted, deficiency of FAT CD36 has been genetically linked to insulin resistance in the SHR. In humans, incidence of CD36 deficiency ranges between 0.3 to 18.5 and is highest in subpopulations with high rates of diabetes type II. We examined insulin responsiveness of the CD36-null mouse, which would represent a good model of the CD36-deficient human in terms of the magnitude of the defect in FA uptake 118 . The CD36- - mouse fed a chow diet rich in complex carbohydrates and low (5 ) in fat was more insulin-sensitive than the wild-type control. It cleared glucose faster, reflecting a several-fold enhancement in glucose utilization by muscle. In vitro, insulin responsiveness of glycogenesis by the null soleus was enhanced. However, when the chow diet was switched to one high in fructose, the CD36- - but not the wild-type mouse developed marked glucose intolerance and hyperinsulinemia, reflecting decreased muscle glucose uptake. Both mice groups had glucose intolerance with...

Cytokines and Insulin Resistance

In addition to their well-known anorectic and hypermetabolic effects, cytokines appear to be involved in obesity-related disorders such as insulin resistance and vascular diseases 65 . Epidemiological findings support the hypothesis that the metabolic syndrome, type II diabetes and cardiovascular diseases have an inflammatory component mediated by cytokines 66, 67 . Thus, overweight and obese children as well as adults TNF-a was among the first substances to be implicated in fat cell insulin resistance 68 . Adipose tissue TNF-a expression is increased in obese subjects, and TNF-a may limit an increase in adipocyte size by inhibiting lipoprotein lipase (LPL) and increasing insulin resistance 68 . A p55 TNF-a receptor-mediated phosphorylation of serine residues on the insulin receptor substrate-1 (IRS-1) appears to be an important mechanism for the induction of insulin resistance by TNF-a 69, 70 . The genetic deficiency of TNF-a or TNF-a signalling resulted in improved insulin...

Criteria for the Diagnosis of Diabetes

According to the WHO, the ADA (American Diabetes Association), the IDF (International Diabetes Federation), and the ALFEDIAM (Association de Langue Fran aise pour l'Etude du DIAb te et des maladies M taboliques),7-10 the criteria for diagnosis are or, symptoms of diabetes (such as polyuria, polydipsia, weight loss) and casual plasma glucose level > 200 mg dL. More recently, criteria for the diagnosis of a syndrome of insulin resistance close to type 2 diabetes, the metabolic syndrome, have been defined. According to the experts of the National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP)-III, three of the following five items are needed for diagnosis of metabolic syndrome11 Nutrition counseling for patients with the metabolic syndrome is described in Chapter 25. As far as diabetes mellitus is concerned, three kinds of diabetes exist Type 1 diabetes due to pancreatic beta-cell destruction leading to absolute insulin deficiency. The major cause of type 1 diabetes...

Nutritional Intervention to Prevent Type 2 Diabetes in Overweight Obese Subjects

Because much of the risk of developing type 2 diabetes is attributable to obesity,10 maintenance of a healthy body weight is strongly recommended as a means of preventing this disease. The relationship between glycemic index and glycemic load and the development of type 2 diabetes remains unclear at this time.9 Studies have been initiated in the last decade to determine the feasibility and benefit of various strategies to prevent or delay the onset of type 2 diabetes. A majority of subjects included in these trials were overweight obese and had impaired glucose tolerance. In well-controlled studies that included a lifestyle intervention arm, substantial efforts were necessary to achieve only modest changes in weight and exercise, but those changes were sufficient to achieve an important reduction in the incidence of diabetes (58 in both the Finnish Diabetes Prevention Study and the US Diabetes Prevention Program). In the Finnish Diabetes Prevention Study,11 weight loss average 4.6kg...

Insulin and Diabetes Mellitus

Energy reservoirs in humans are built up and broken down in response to hormonal messages. Insulin is the principal hormonal messenger and has an anabolic effect. It is a major regulator of glycogen storage and its most important action is to enhance glycogen synthesis 2,3 . In the metabolism of fat, insulin inhibits lipolysis and induces the storage of triglycerides in adipose tissue 4 . Diabetes mellitus is a syndrome characterised by chronic hyperglycaemia and disturbances of carbohydrate, fat, and protein metabolism associated with absolute or relative deficiencies in insulin secretion and or insulin action. Diabetes mellitus has been classified into four groups type 1, type 2, other specific types, and gestational diabetes. Type 1 diabetes results from destruction of the beta-cells of the pancreas, usually leading to absolute insulin deficiency. There are two forms of type 1 diabetes, immune-mediated diabetes and idiopathic diabetes. Type 2 diabetes refers to individuals who have...

Protein Metabolism in Diabetes Mellitus

Animal and in vitro studies have shown that insulin inhibits muscle protein breakdown and enhances protein synthesis 16,17 . The results of studies performed in humans do not always agree with those conducted in vitro and in vivo in animals. In human studies, whole-body protein synthesis is estimated by measuring the nonoxidative disposal of branched-chain, essential amino acids during the primed constant infusion of 1-13C Leu or 1-14C Leu. Protein breakdown is usually estimated from the release into plasma of essential amino acids, such as leucine or phenylalanine, while net protein loss is determined from the irreversible loss of any essential amino acid that occurred by oxidation or hydroxylation. Increased rates of leucine flux were found in type 1 diabetic patients, indicating increased protein breakdown. Leucine oxidation also increased, suggesting increased net protein loss. In contrast, the rate of non-oxidised leucine disposal, i.e. the fraction of leucine entering protein,...

Malnutrition Related Pancreatic Diabetes Mellitus

In tropical countries, there is another type of diabetes with many atypical clinical features. Hugh-Jones, in Jamaica, described the features of this type of diabetes and named it type J diabetes 32 . The features of this type include early-age onset of diabetes, a lack of ketosis, a relatively large insulin requirement, and lean body. Although many variants have been reported, the common features of this type of diabetes are malnutrition and protein deficiency. In 1985, a World Health Organisation study group identified two main subgroups of pancreatic diabetes protein-deficient diabetes mellitus (PDDM), and fibrocalculous pancreatic diabetes (FCPD). In patients with the latter, there was no history of alcohol, biliary disease, or other known cause of pancreatitis. Clinically, malnutrition-related diabetes differs from chronic alcoholic pancreatitis in several respects. The disease occurs at an earlier age (usually before age 30) and is related to malnutrition, particularly in...

Defects of skeletal muscle glucose metabolism in insulin resistant states

Using the above mentioned methods, studies on skeletal muscle glycogen synthesis in insulin resistant populations revealed 60 decrease of insulin stimulated glycogen synthesis in overt T2DM patients (Shulman et al. 1990) (Figure 11.6) as well as 70 decrease in their lean insulin resistant offspring (Rothman et al. 1995). The same defect was found in obese non-diabetic insulin resistant volunteers (Petersen et al. 1998a). Further, defects in the insulin dependent phase of glycogen resynthesis that follows the depletion of glycogen stores by exhausting exercise were found in the insulin resistant offspring of T2DM patients (Price et al. 1996) decreased postprandial skeletal muscle glycogen synthesis in normal physiological conditions after a mixed meal was found in T2DM patients by the same method (Carey et al. 2003). Increase of glucose-6-phosphate concentration during hyperinsulinaemic-euglycaemic clamp is blunted according to the extent of insulin resistance in all insulin resistant...

Mitochondrial function in insulin resistant states

Shifting the focus down the metabolic pathways to the point where lipid and glucose oxidation meet in cell, it was hypothesised that mitochondrial oxidative and phosphorylation capacity might be a contributing factor to insulin resistance and increased intracellular lipid storage intramyocellular lipid (IMCL) content (Shulman 1999). One of the key intermediate metabolites of lipid oxidation long-chain acyl-CoA was found to be involved in the regulation of glycogen synthase (Wititsuwannakul & Kim 1977) and glucokinase (Tippett & Neet 1982) reactions and in the modulation of PCK isoforms (Faergeman & Knudsen 1997), and correlated with whole body insulin sensitivity (Ellis et al. 2000). In accordance with previous results, recent MRS studies have found that skeletal muscle mitochondrial oxidative and phosphorylation capacity is associated with a decrease of peripheral insulin sensitivity and an increas in intramyocellular lipid content in elderly sedentary individuals (Petersen...

Defects of hepatic glucose metabolism in diabetes mellitus

Turning our attention to hepatic glucose fluxes following a normal meal in type 1 and type 2 diabetic patients, studies have revealed significant alterations of hepatic glycogen storage (Figure 11.12), glycogen release and gluconeogenesis in both patient groups (Taylor et al.1996 Hundal et al. 2000 Bischof et al. 2001, 2002 Singhal et al. 2002 Krssak et al. 2004). A defect in hepatic glycogen storage was observed in glucokinase deficient maturity-onset diabetes of the young 2 (MODY-2) patients, in whom the impaired hepatic glucokinase activity is held responsible for a reduction in the contribution of glucose (the direct pathway) to hepatic glycogen synthesis (Velho et al. 1996). Lower glycogen synthesis (Bischof et al. 2001, 2002 Krssak et al. 2004) and unsatisfactory suppression of endogenous glucose production (Sinha et al. 2002 Krssak et al. 2004) contribute to postprandial hyperglycaemia in both pathologies. Increased gluconeogenesis is the key to postabsorptive hyperglycaemia in...

HsCRP Metabolic Syndrome and Type 2 Diabetes Mellitus

Clinical practice, such as elevated triglycerides, low HDL-C, obesity, high fasting glucose, and high blood pressure (BP). In the Women's Health Study, e.g., after adjustment for multiple potential confounders, the RRs of incident hypertension for increasing hsCRP quintiles were 1.00 (referent), 1.07 (95 CI 0.95-1.20), 1.17 (95 CI 1.04-1.31), 1.30 (95 CI 1.17-1.45), and 1.52 (95 CI 1.36-1.69), respectively (p for trend of < 0.001) (73). hsCRP levels are also correlated with other components of the syndrome not easily assessed during routine office visits, such as fasting insulin, microalbuminuria, and impaired fibrinolysis. Indeed, among Women's Health Study participants without diabetes, hsCRP and BMI were the only independent correlates of fasting insulin level modeled as a continuous dependent variable. After adjustment for BMI and other risk factors for diabetes, the RR for elevated fasting insulin ( 51.6 pmol L) increased with the tertile of hsCRP (for hsCRP < 1.4, 1.4-4.4,...

Methodology For Diabetes And Exercises

Describe the Clinical Practice Guidelines of the American Diabetes Association for the diagnosis of type 1 diabetes, type 2 diabetes, and gestational diabetes. 3. Describe the evidence that indicates that control of blood glucose levels will reduce the severe consequences of diabetes. 4. Explain the use of the measurement of Hb A1c levels in the diagnosis and treatment of diabetes. 1. American Diabetes Association Diabetes statistics. Available at http www.diabetes.org diabetes-statistics.jsp (accessed Feb 13, 2006). 2. Diabetes Surveillance. Bethesda, MD U.S. Department of Health and Human Services, 1999. 4. Dokhee TM An epidemic of childhood diabetes in the United States Evidence from Allegheny County, Pennsylvania. Pittsburgh Diabetes Epidemiology Research Group. Diabetes Care 1993 16 1606-1611. 5. American Diabetes Association Diagnosis and classification of diabetes mellitus. Diabetes Care, 2006 29(Suppl 1). 6. Clark PM Assays for insulin, proinsulin(s) and C-peptide. Ann Clin...

Leptin Interacts with Ghrelin and Insulin

Leptin and insulin interact with each other. Insulin plays a major role in the regulation of lep-tin production, stimulating the transcriptional activity of the leptin promoter, increasing leptin gene expression and elevating leptin circulating concentrations. These effects are all mediated by actions of insulin to promote glucose uptake and oxidative metabolism in adipocytes 50 . On the other hand, leptin can down-modulate insulin signalling in adipocytes in two different ways. Leptin may modulate the pancreatic insulin and glucose homeostasis acting in the hypothalamus throughout the activation of neuronal circuits and the autonomic nervous system 49 , but it also exerts a direct effect on the adipocytes. In animals with elevated serum leptin concentrations, leptin inhibits insulin signalling, impairing insulin receptor autophosphorylation. This modulation of adipocyte insulin signalling could be relevant in physiological situations of hyperlepti-naemia and central leptin...

Prediabetes And Metabolic Syndrome

Prediabetes is defined by results of laboratory analysis for fasting glucose that fall into the impaired fasting glucose range, or by results of laboratory analysis for a 2hour glucose challenge that fall into the impaired glucose tolerance range, or by laboratory results that exhibit both impaired fasting glucose and impaired glucose tolerance (Table 10-7). Impaired fasting glucose is defined as a glucose level that is above the upper limit of normal and below the lower limit that defines diabetes, 100 to 125 mg dL. Impaired glucose tolerance is defined as a glucose level that is above the upper limit of normal and below the lower limit that defines diabetes, 140 to 199 mg dL. The term prediabetes is now preferred over impaired fasting glucose or impaired glucose tolerance.19 The American Diabetes Association recommends screening for prediabetes for individuals who are 45 years old or older and have a BMI that suggests obesity (BMI > 25 kg m2). Screening is also suggested for...

Growth Hormone InsulinLike Growth Factor1 Axis

Interest in the growth hormone insulin-like growth factor-1 (GH IGF-1) axis as a mediator of aging-related changes in the brain and other organ systems developed from the recognition that a substantial decline in serum GH and IGF-1 levels is one of the most robust hallmarks of mammalian aging (reviewed in 105-107 . Given the pleiotropic effects of IGF-1 in the brain and increasing evidence that GH has direct effects in the brain, as well as regulating IGF-1 levels, it is reasonable to expect that the aging-related decline in GH IGF-1 activity is significant for brain structure and function. There is experimental evidence that restoring GH and or IGF-1 in older animals ameliorates many aging-related neural changes (105, 107). With respect to neurogenesis, several lines of evidence implicate the GH IGF-1 axis in aging-related changes. The regulation of adult neurogenesis appears to be linked to the regulation of angiogenesis (e.g., 87, 90, 108 ), which is modulated in the aging brain by...

Application of muscle morphology in type 2 diabetes

Insulin resistance and type 2 diabetes are associated with a number of morphological characteristics in skeletal muscle. In humans, muscle fibre composition is more mixed than in rodents (Johnson et al. 1973). This has implications for many biochemical and metabolic abnormalities observed in studies of crude muscle extracts, as the functional and metabolic properties of muscle are to a large extent determined by its fibre type composition. Using the In most (Marin et al. 1994 Gaster et al. 2001) but not all (Zierath et al. 1996) studies, a lower proportion of type 1 muscle fibres and a higher proportion of type 2 (particularly 2b) muscle fibres have been reported in type 2 diabetes. Furthermore, histochemical studies have shown a lower capillary density in skeletal muscle in type 2 diabetes (Marin et al. 1994). Using electron microscopy and stereology we have found an increased intramyocellular lipid content (IMCL) and a lower muscle glycogen content in type 2 diabetes (Levin et al....

Application of myotubes in diabetes research

In human myotubes established from skeletal muscle biopsies of both healthy subjects and patients with type 2 diabetes, we have used a variety of approaches to study possible mediators of insulin resistance under both physiological and so-called 'inducing' conditions (Table 14.2). This includes biochemical determination of 1) glucose, G6P, glycogen and triacylglycerol (TAG) (Gaster et al. 2001c, 2002, 2004 Kase et al. 2005) 2) activity, kinetics and or protein expression of distal components of the insulin signaling cascade such as GS and GSK-3 (Gaster et al. 2001c, 2002, 2004) and 3) other enzymes essential for glucose and lipid metabolism such as hexokinase (HK), citrate synthase (CS), CK and 3-hydroxy-acyl-CoA dehydrogenase (HAD) (Gaster et al. 2001a,b Ortenblad et al. 2005) as well as 4) gene expression analysis in myotubes using both the cDNA microarray technique and real time (RT)-PCR reactions (Hansen et al. 2004 Abdallah et al. 2005 Kase et al. 2005). Moreover, we have...

Major data and relevance to better understanding of diabetes and metabolism

Several studies in diabetic patients revealed the effects of lifestyle modification or physical exercise on endothelial function. In insulin-resistant subjects, lifestyle modification with exercise and weight reduction over six months improved endothelial function (Hamdy et al. 2003). Interestingly, the relationship between percentage weight reduction and improved FMD was linear. A similar result was seen in patients with type 2 diabetes (Maiorana et al. 2001). Likewise, in patients with type 1 diabetes, FMD could be improved by four months of bicycle exercise (Fuchsjager-Mayrl et al. 2002). However, the positive training effect on endothelial function was not maintained after cessation of regular exercise (Figure 15.5). In all studies, GTN-mediated dilation was unaffected by exercise. Another interesting study assessing FMD in 75 children with type 1 diabetes revealed that even children with diabetes have impaired endothelial function compared to healthy controls (Jarvisalo et al....

Major data relevance to better understanding of diabetes and metabolism

One of the advantages of IMT measurements is that they can be performed quickly and easily by an experienced observer. Thus, large trials can be performed. IMT measurements are suitable for assessing the incidence of early stages of atherosclerosis in patients with diabetes. Accordingly, in a smaller study including 229 patients with type 2 diabetes, IMT was shown to be an independent predictor of cardiovascular events (Bernard et al. 2005). The odds ratio for cardiovascular events per SD increase in carotid IMT was 1.63 (95 CI 1.01-2.63). In contrast to the methods that estimate endothelial function, described above, IMT assesses a more advanced stage of atherosclerosis, in which structural changes of the vascular wall are already demonstrable. Nevertheless, therapeutic intervention studies have shown that enhanced IMT is at least partially reversible in patients with diabetes. An example for such an intervention study is that by Langenfeld et al. (2005) in patients with type 2...

Micronutrients Diabetes

To enhance the action of insulin and help control blood glucose Can enhance insulin sensitivity and reduce needs for oral hypoglycemics and or insulin.5-7 Reduces platelet aggregation and risk of thrombosis As a component of GTF, helps control blood glucose and decrease need for insulin or hypoglycemic drugs.1-3 Can be taken together with 5-10 g brewer's yeast Magnesium deficiency is common in diabetes. Supplements may help control blood glucose and protect against cardiovascular disease11 Helps replenish urinary losses To help control newly-diagnosed type 1 diabetes Niacinamide 1-3 g begin with 500 mg day Supplements in newly diagnosed type 1 diabetes can reduce insulin requirements and extend the time before beginning insulin.15 Avoid nicotinic acid, anotherform of niacin, which can be harmful in diabetics

Periodontal Disease And Diabetes Mellitus

The relationship between diabetes mellitus and periodontal disease has been extensively examined. It is clear from epidemiologic research that diabetes increases the risk for and severity of periodontal diseases. I he biologic mechanisms through which diabetes influences the periodontium are discussed in Chapter 12. t he increased prevalence and severity of periodontitis commonly seen in patients with diabetes, especially those with poor metabolic control, led to the designation of periodontal disease as the sixth complication of diabetes.35 In addition to the five classic complications of diabetes (Box 13-2), the merican Diabetes Association has officially recognized that periodontal disease is common in patients with diabetes, and its Standards of Care include taking a history of current or past dental infections as part of the physician's examination. '1 Although many studies have examined the effects of diabetes on the periodontium, fewer have endeavored to examine the effect of...

Laboratory Results In Type 1 Diabetes

A brief examination of the laboratory results in this case suggests an individual with poor glucose control over a long period of time who was experiencing an acid-base imbalance. The increased plasma glucose, serum ketones, whole plasma lactate, urine glucose, and urine ketones were typical of uncontrolled type 1 diabetes. The decreased CO2 suggested an acid-base disturbance, most likely metabolic acidosis. The increased anion gap suggested the existence of unmeasured anions, most likely keto acids, in Brandon's blood. The laboratory results for serum and urine ketones also suggested an acid-base imbalance. Ketoacidosis is one form of metabolic acidosis that occurs in response to a patient's inability to metabolize glucose for energy.15 The enzymes that metabolize glucose are present in most cells, but not in the extracellular fluid. Without the action of insulin, glucose cannot enter the cell. In the absence of cellular glucose, fatty acids are oxidized for production of energy....

Protein Kinase B and the Glucose Transporter How Insulin Works

Figure 16.10 shows the insulin receptor. Like other receptor tyrosine kinases, the insulin receptor has an extracellular domain that can bind the transmitter, in this case the protein insulin, a single polypeptide chain that crosses the plasma membrane, and a cytosolic domain with tyrosine kinase activity. Unlike growth factor receptors, the insulin receptor exists as a dimer even in the absence of its ligand, insulin. When insulin binds, the shape and orientation of the individual insulin receptors change a little, and this allows each receptor to phosphorylate its partner upon tyrosine. An associated protein called the insulin receptor substrate number 1 (IRS-1) is also phosphorylated on tyrosine. Proteins with SH2 domains are therefore recruited, either to the phosphorylated tyrosines on the insulin receptors themselves or to the phosphorylated tyrosines on IRS-1. The most important protein to be recruited is phosphoinositide 3-kinase (PI 3-kinase). Binding to the phos-phorylated...

Insulinlike Growth Factors

The discovery of IGFs came about from a variety of approaches but initially from the identification of insulin-like activities in plasma or serum. At first these activities had various names such as nonsuppressible insulin-like activities, A group of polypeptides present in plasma that have insulin-like activity but could not be neutralized by antibodies directed against insulin, called the nonsuppressible insulin-like activities (NSILA), were separated into two fractions NSILA-P, which was precipitable by ethanol at low pH, and NSILA-S, which was soluble under these conditions. Two peptides of about 7000 MW with mitogenic activity were isolated from the NSILA-S fraction.195 These have now been called insulin-like growth factors 1 and 2 (IGF-1 and IGF-2).

Treatment of Diabetes Mellitus

Intensive control of blood glucose prevents the microvascular complications of diabetes, but its effect on macrovascular complications is less certain. The Diabetes Control and Complications Trial comparing intensive and conventional insulin therapy in 1441 patients with type 1 diabetes showed an association of intensive therapy with a trend toward a reduction in cardiovascular events (P 0.08) but no effect on the risk of peripheral arterial disease was noted.5 The results were similar in 3867 patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study, which compared intensive drug treatment using sulfonylurea or insulin with dietary therapy.6 Intensive drug therapy was associated with a trend toward a reduction in myocardial infarction (P 0.05) but had no effect on the risk of death or amputation due to peripheral arterial disease (relative risk 0.6 95 confidence interval, 0.4 to 1.2). These data suggest that intensive blood glucose control in patients with either...

Congenital Generalised Lipodystrophy Berardinelli Seip Syndrome or Lipoatrophic Diabetes

Lawrence Syndrome Lipodystrophy

A patient with congenital lipodystrophy or lipoatrophic diabetes. There is evidence of a pronounced loss of subcutaneous fat, acromegaloid aspect, and phlebomegaly (for details, see Table 3, patient GF) Fig. 2. A patient with congenital lipodystrophy or lipoatrophic diabetes. There is evidence of a pronounced loss of subcutaneous fat, acromegaloid aspect, and phlebomegaly (for details, see Table 3, patient GF) plasma levels, hypertrichosis, mild virilisation, liver enlargement, reduced glucose tolerance or overt diabetes, heat intolerance, and increased perspiration (Table 2) 21-23 . Insulin resistance CGLD can manifest with different expression of signs and symptoms and with different degrees of severity of the metabolic abnormalities (Table 3). Insulin resistance usually evolves into overt diabetes. Micro- and macroangiopathies and keto-sis are unusual in lipoatrophic diabetes. An increased resting energy expenditure without abnormalities of thyroid function has been...

Differences Between Human And Animal Insulins

Human insulin is absorbed from subcutaneous tissue slightly more rapidly than animal insulins and it has a slightly shorter duration of action. Human insulin is less immunogenic than bovine, but not porcine, insulin. When changing from animal to human insulin, patients taking < 100 units of animal insulin are likely to require 10 less human insulin, and if taking > 100 units animal insulin, 25 less human insulin. There has been concern that patients taking human insulin may experience more frequent and more severe hypoglycaemic attacks, especially when 3 Peak plasma insulin (s.c.) concentration is attained in 60-90 min. Absorption is slower if there is peripheral vascular disease or smoking, and faster if the patient takes a hot bath or uses an ultraviolet light sunbed (which may induce a hypoglycaemic fit) or exercises. The effects are due to changes in peripheral blood flow. transferring from animal insulins. Such occurrences are likely to be due to management problems rather...

Adverse Effects Of Insulin

Adverse effects of insulin are mainly those of overdose.6 Because the brain relies on glucose as its 6 Suicidal overdose (in diabetics) is well recorded. Surgical excision of the skin and subcutaneous tissue at the injection site of an enormous dose of long-acting insulin has been used effectively. source of energy, an adequate blood glucose concentration is just as essential as an adequate supply of oxygen, and hypoglycaemia may lead to coma, convulsions and even death (in 4 of diabetics under 50 years of age). It is usually easier to differentiate hypoglycaemia from severe diabetic ketosis than from other causes of coma, which are as likely in a diabetic as in anyone else. It is unsound to advocate blind administration of i.v. glucose to comatose diabetics on the basis that it will revive them if they are hypoglycaemic and do no harm if they are hyper-glycaemic. A minority of comatose insulin-dependent diabetics have hyperkalaemia and added glucose can cause a brisk and potentially...

Insulin Resistance And Hormones That Increase Blood Glucose

Insulin resistance may be due to a decline in number and or affinity of receptors (see above) or to defects in postreceptor mechanisms. A diabetic patient requiring more than 200 units day is rare and regarded as insulin resistant (occasional patients have needed as much as 5000 units day). Insulin resistance has become much less frequent with the wide availability of purified, mono-component and human insulins. If the requirement is acquired and genuine, it is due to antibodies binding insulin in a biologically inactive complex (though it can dissociate as with protein binding of drugs). De novo insulin resistance occurs in a small number of genetic syndromes, e.g. in combination with the skin condition acanthosis nigricans. 7 In the early stages of insulin treatment, it can be very useful training to allow a patient to experience hypoglycaemia once by delaying a meal. Where animal insulins are still in use, change to a highly purified pork or human insulin may be successful in...

Oral antidiabetes drugs

Oral antidiabetes drugs are of two kinds sulphon-amide derivatives (sulphonylureas) and guanidine derivatives (biguanides). They are used by 30 of all diabetics. Unlike insulin they are not essential for life. Following the observation in 1918 that guanidine had hypoglycaemic effect, guanides were tried in diabetes in 1926, but were abandoned a few years later for fear of hepatic toxicity.

Box 3 Unique factors in diabetics that affect stress test results

Females with diabetes Lower predictability of traditional also been an acceptable tool for detection of CAD in diabetic patients. A retrospective review of diabetic patients who underwent myocardial perfusion imaging followed by cardiac catheteri-zation reported a sensitivity of 97 and positive predictive value of 88 for CAD 43 . Kang and colleagues 44 reported a similarly high sensitivity (86 ) but a specificity of 56 in a similar patient population. These studies support a detection rate for CAD by stress scintigraphy, but specificity of the method may be limited in diabetic patients. Myocardial stress scintigraphy has also provided prognostic information. Berman and colleagues 45 evaluated 2826 patients who underwent adenosine myocardial perfusion imaging. They noted that diabetics who had an abnormal perfusion scan were at a significantly increased risk of death compared with nondia-betics and that perfusion imaging data was an independent predictor of events. Including diabetic...

Some Factors Affecting Control Of Diabetes

An appropriate starting dose is biphasic (mixtard) insulin 10-15 units twice daily. Infections cause an increase in insulin need (about 20 ), which may drop briskly on recovery. In patients with poor glycaemic control, it is preferable to use an insulin infusion and sliding scale, as described below for diabetic ketosis. Menstruation and oral contraception insulin needs may rise slightly. Use of glucocorticoids insulin needs are increased. In pregnancy close control of diabetes is of the first importance to avoid fetal loss at all stages, and in the first trimester to reduce fetal malformations. Insulins requirements increase steadily after the third month. Ideally, women of childbearing age should be advised to conceive during a period of stable, euglycaemic control. During labour soluble insulin should be given by continuous infusion at about l-2unit h with i.v. infusion of 5 glucose 1.0 litre in 8 h). Substantially less, e.g. 25 , insulin is likely to be...

Calpain 10 and type 2 diabetes

In the first successful genome-wide scan of a complex disease like type 2 diabetes, Graeme Bell and co-workers reported significant linkage (LOD 4.1 p < 10-4) between type 2 diabetes in Mexican American sib pairs and a locus on chromosome 2q37, called NIDDM1 (Hanis et al. 1996). Still, this region was quite large (12 cM), encompassing a large number of putative genes. A re-examination of the data suggested an interaction (epistasis) with another locus on chromosome 15 (with a nominal LOD of 1.5). This enabled the researchers to narrow the region down to 7cM. Luckily, because it is telomeric with a high recombination rate, the 7cM genetic map only represents 1.7 megabases of physical DNA. To clone the underlying gene, they genotyped 21 SNPs in this 7 cM interval and identified a three-marker haplotype that was nominally associated with type 2 diabetes. At the end, three intronic SNPs (43,44 and 63) in the gene encoding for calpain 10 (CAPN10) could explain most of the linkage...

Interactions With Nondiabetes Drugs

Fi-adrenoceptor blocking drugs impair the sympathetic mediated (p2-receptor) release of glucose from the liver in response to hypoglycaemia and also reduce the adrenergic-mediated symptoms of hypoglycaemia (except sweating). Insulin hypoglycaemia is thus both more prolonged and less noticeable. A diabetic needing P-adrenoceptor blocker should be given a Pj-selective member, e.g. bisoprolol. Thiazide diuretics at a higher dose than generally now used in hypertension can precipitate diabetes, and it is wise to use low doses especially in established diabetes. Monoamine oxidase inhibitors potentiate oral agents and perhaps also insulin. They can also reduce appetite and so upset control. Salicylates and fibrates can increase insulin sensitivity.

The Diabetes Simulating Model

A hypothetical medical condition was constructed to roughly resemble type 1 (juvenile) diabetes a condition that arises in childhood in which the body becomes unable to generate insulin, leading to sugar imbalances. People with type 1 diabetes can encounter a range of serious, ultimately life-threatening complications. Stem cell therapy appears to be effective for the treatment of type 1 diabetes. An important potential benefit of stem cell therapy is a reduction in mortality for individuals with this condition. To quantify its possible effect, an example survival curve was designed for type 1 diabetes. For simplicity, it was assumed that there are 1000 new cases diagnosed among children per year, and that these diagnoses occur among children at age 10. The survival curves were designed, beginning with the US population mortality rates by age for 2001, assuming that mortality rates for the simulated condition are seven times higher than that for the overall population (Fig. 2). This...

Diabetes Insipidusvasopressin Deficiency

Diabetes insipidus (DI) can be due to either pituitary or renal causes. The pituitary may be damaged by trauma, tumours, haemorrhage or infarction. Nephrogenic DI has a larger number of causes including drugs (lithium, demeclocycline) and several diseases affecting the renal medulla. The DNA sequencing of the preceptor and aquaporins has also allowed identification of mutations in these which cause congenital DI. Desmopressin replacement therapy is the first choice. Thiazide diuretics (and chlortalidone) also have paradoxical antidiuretic effect in diabetes insipidus. That this is not due to sodium depletion is suggested by the fact that the nondiuretic thiazide, diazoxide (see Index), also has this effect. It is probable that changes in the proximal renal tubule result in increased reabsorption and in delivery of less sodium and water to the distal tubule, but the mechanism remains incompletely elucidated. Some cases of the nephrogenic form, which is not helped by antidiuretic...

LXRs as Insulin Sensors in Liver

Insulin is probably the most important hormonal factor influencing lipogenesis. It is known that both glucose and insulin are required for the production of fatty acids via the induction of hepatic lipogenic enzymes. The main role of insulin is to maintain the blood glucose concentration nearly constant in the face of large fluctuations in the dietary intake of glucose. Different groups have shown that SREBP-1c is upregulated by insulin in vivo and in primary hepatocyte cultures 64-66 . These observations raised a possibility that SREBP-1c could be a metabolic mediator of insulin action in the liver 67 . However, there are reports indicating that SREBP-1c is not the only transcription factor involved. In refed SREBP-1c- - mice some hepatic lipogenic enzyme genes were completely abol ished, whereas others were only partially suppressed, indicating that other factors in addition to SREBP-lc might be involved in the refeeding response 68 . A recent study has also demonstrated a...

Impaired Insulin Secretion

The pancreatic beta-cell has the ability to sense glucose levels in order to adapt insulin secretion to blood glucose fluctuations. This is accomplished by the expression of a particular profile of carbohydrate transporters and enzymes in the beta-cell 19 . There is substantial knowledge about the molecular mechanism of glucose metabolism in the beta-cell and how this metabolism is coupled to insulin secretion. However, our understanding is still incomplete. For example, the precise role of mitochondrial metabolism and mitochondrial messengers in the stimulation of insulin exocytosis is only starting to emerge 20 . T2DM is characterized by a progressive loss of beta-cell function. An initial defect is the near-absent first-phase glucose-induced insulin secretion, followed by impaired second-phase insulin secretion and increased release of pro-insulin relative to insulin (hyperproinsulinemia). Last, defective basal insulin secretion develops, leading to complete beta-cell failure. Any...

Impaired Insulin Action Insulin Resistance

As outlined in the section on glucose homeostasis, in the healthy state, insulin promotes glucose uptake in the peripheral target tissues skeletal muscle and adipose tissue. In addition, insulin inhibits glucogenolysis and gluconeogenesis in the liver. In the case of insulin resistance, the ability of insulin to activate its signaling pathways is reduced. Consequently less glucose is taken up by the target tissues and basal hepatic glucose production is increased. Interestingly, insulin sensitivity varies widely in the normoglycemic population. For normal beta-cell function, insulin resistance may be present for many years before the onset of overt hyperglycemia, because of a compensatory secretory response of the beta-cell. However, in individuals predisposed to T2DM, beta-cells either fail to compensate the developing insulin resistance or fail after compensating for some time due to exhaustion. Any defect in the control of hepatic glucose production and or peripheral glucose uptake...

The Treatment of Diabetes Mellitus

The goal of a diabetes treatment seems simple, a tight control of the blood glucose levels is sufficient. However, consideration of the complex regulation of blood glucose in humans clearly indicates that a tight control of blood glucose is not an easy task. In T1DM plasma insulin levels are low or absent and treatment with insulin is always necessary. Since it is not yet possible to mimic the normal function of a beta-cell, which precisely adjusts the rate of insulin secretion in response to biological needs, the treatment ofT1DM is complicated by episodes of hypoglycemia and hyperglycemia. Hypoglycemia can cause coma, and hyperglycemia increases the risk for diabetic complications in the form of eye disease, kidney disease, nervous system damage, and coronary artery disease and stroke 69 . In T2DM there is a wide spectrum in the degree of impaired insulin secretion and action. First, patients are separated into an obese and non-obese group, because weight loss is a crucial factor 70...

Proteomics a Global Approach to the Study of Diabetes Mellitus

Proteomic approaches aim at the qualitative and quantitative comparison of pro-teomes under different conditions. A proteome is the ensemble of proteins expressed by a genome of a species, an organ, or a cell at a particular moment under particular conditions. Approaches include comparative analysis of global protein expression in normal and disease tissues to identify aberrantly expressed proteins. In the recent years, several groups took advantage of the power of a proteomic approach for their studies in the field of diabetes. Most studies have been car ried out in rodent animal models of diabetes. Because of species differences between humans and rodents, especially in adipocyte function 50 , an increased use of human samples from diabetic patients would be desirable.

Type 1 Diabetes Mellitus

A series of proteomic studies were performed aiming at the identification of proteins with possible deleterious and protective roles in the initial cytokine-induced beta-cell damage in T1DM. The cytokine IL-1 5 inhibits insulin release and is selectively cytotoxic to beta-cells in isolated pancreatic rat islets. IL-1 5 induces nitric oxide (NO) via the enzyme inducible nitric oxide synthase (iNOS) and NO seems to be a major effector molecule in IL-1 5-induced beta-cell damage. For the proteo-mic studies, pancreatic islets isolated from neonatal Wistar Furth (WF) rats were incubated in the presence and absence of IL-1 5. In addition, inhibitors of NO production as well as chemically generated NO were used. Since de novo protein synthesis was shown to be necessary for the deleterious effect of IL-1 5, islets were metabolically labeled with 35S methionine. Finally, islet proteins were separated by two-dimensional (2-D) gel electrophoresis. Overall, 105 protein spots were found to be...

Type 2 Diabetes Mellitus

A mouse Swiss 2-D PAGE database has been established 89 . It contains a number of 2-D gel electrophoresis reference maps with protein identifications from mouse white and brown adipose tissue, pancreatic islets, liver and skeletal muscle. These maps can be accessed through the internet (http us.expasy.org cgi-bin map1) and represent a valuable tool for further proteomic studies of diabetes and obesity. 218 12 Diabetes Mellitus Complex Molecular Alterations 12.4.2.1 Muscle In order to investigate the molecular alterations associated with insulin resistance in muscle tissue, human skeletal muscle biopsies from patients with T2DM and from healthy controls were compared by 2-D gel electrophoresis 90 . Eight potential protein markers were identified. ATP synthase 5-subunit was found to be down-regulated in skeletal muscle of patients with T2DM. In addition, the levels of a phosphoisoform of the down-regulated ATP synthase 5-subunit correlated inversely with fasting plasma glucose levels in...

Diabetes and Metabolic Syndrome

The relationship between diabetes and cancer is the focus of a lot of attention. This interest is often expanded to include the metabolic syndrome. Two parallel definitions of the latter exist. The Guidelines from the National Cholesterol Education Program (Adult Treatment Panel ATP III)7 require the presence of any three of the following * Some men can develop multiple metabolic risk factors when waist circumference is only marginally increased 94 to 102 cm (37 to 39 in) as such patients may have a genetic contribution to insulin resistance. The association of diabetes mellitus and cancer has been most studied in the case of colorectal cancer. Diabetic patients have an increased incidence of colorectal cancer 9-11. A recent study highlights that diabetes is also associated with a shorter disease-free survival (Figure 1) 12. Another study focused on patients undergoing hepatic colorectal cancer metastasis resection 13. Diabetic patients had a higher peri-operative mortality (8 versus...

Diabetes Prevention in the NOD Mouse

There are literally over 100 therapies known to prevent diabetes in the NOD mouse (1). Some agents used in the mouse model have included immunosuppressive drugs such as azathioprine, corticosteroids, cyclophosphamide, cyclosporin, and methotrexate. These agents generally have nonspecific immune activities that do not target specific autoreactive T lymphocytes. Furthermore, they do not appear to be effective over the long term, with disease recurrence once the drug is withdrawn. Finally, antigen-specific therapy is under study in type 1 diabetes and other autoimmune diseases for which the autoantigens have been identified. Potential autoantigens include insulin B-chain and insulin B 9-23 peptide, GAD, and heat shock protein (p277 peptide of HSP60). Autoantigen peptide vaccination is perhaps the most specific type of immunotherapy in both humans and the mouse, but has properties of a double-edged sword although such therapy may prevent diabetes, there is also potential to accelerate or...

See also Action of Insulin Action of Glucagon

Hormones are compounds secreted by specific tissues called endocrine glands (Figure 23.6). Endocrine glands secrete hormones directly into the bloodstream, so the response to a hormonal signal comes as a direct and rapid result of its secretion. Glucagon is a 3.5-kilodalton polypeptide hormone synthesized by the A cells of the islets of Langerhans in the pancreas. These endocrine cells sense the blood glucose concentration and release glucagon in response to low levels (see Figure 23.2 and Table 23.1). Both synthesis and release of glucagon are controlled by insulin.

Peptide Induction Model of Type 1 Diabetes Experimental Autoimmune Diabetes

Diabetes or insulitis can be induced in animals. For example, high doses of streptozotocin can rapidly induce diabetes in several strains of mice (16), and low doses can create a more chronic form of diabetes (17). Administration of polyinosinic polycytidylic acid (poly-IC), which has been used as a viral RNA mimic to stimulate the innate immune system, can induce insulitis and diabetes in RT1u rat strains (18) similar to that seen with the Kilham rat virus (19). We found that immunization with insulin peptide B 9-23 induces IAA expression in normal mice with MHC H-2d and H-2g7 but not H-2b (15) and, if combined with poly-IC, induces insulitis. With the introduction of the B7.1 islet transgene to this model, B 9-23 peptide can induce diabetes (4). In this section, this disease induction model in mice with insulin peptide B 9-23 is described.

See also Action of Insulin Action of Glucagon Hormonal Regulation of Fuel Metabolism Neurotransmitters and Biological

The most important hormone promoting glucose uptake and use is insulin, whereas both glucagon and epinephrine act conversely, to increase blood glucose levels. The major effects of these agents are summarized in Table 23.2. Figure 23.2 illustrates the interplay between insulin and glucagon.

Growth Hormone and Insulin Like Growth Factor1

Growth hormone (GH) and insulin-like growth factor (IGF)-1 stimulate amino-acid uptake and protein synthesis in muscle and improve myocyte proliferation and differentiation in animal studies 106, 107 . The FDA recently granted accelerated approval for a form of recombinant human GH (rhGH) to treat AIDS wasting. Preliminary reports from Schambelan and co-workers in AIDS patients have all been positive 108-112 . The combined GH and IGF-1 doses used in studies in adult males with HIV-associated weight loss had mixed results in producing a sustained anabolic response 113-120 . In fact, after trauma, the anti-catabolic action of rhGH is associated with a potentially harmful decrease in muscle glutamine production and increased mortality 116 . Use of the rhGH for elderly patients with a low somatomedin C or IGF improved lean muscle mass, but not functional ability. Moreover, frequent side effects were seen 121 . Morley and coworkers 122 demonstrated that rhGH, which is a very expensive...

Energy Expenditure in Diabetes Mellitus

Urinary glucose loss may be a more important cause of negative energy balance and weight loss in diabetic patients. However, the basal metabolic rate (BMR) of diabetic patients without glycosuria is higher than that of normal subjects. Increased resting energy expenditure may be another mechanism contributing to weight loss in diabetic subjects, in addition to caloric losses due to glyco-suria. The basal energy expenditure of type 1 diabetic patients (2042 Kcal 24 h) was found to be significantly higher than that of control subjects (1774 Kcal 24 h), and intravenous insulin treatment significantly reduced energy expenditure to 1728 Kcal 24 h, which matched predicted values 7 . The basal energy expenditure of obese subjects with type 2 diabetes was also found to be higher than that of obese subjects with normal glucose tolerance. The mean resting metabolic rate (RMR) of diabetic subjects (32.9 Kcal day kg fat-free mass) was 5 higher than that of nondiabetic subjects (31.4 Kcal day kg...

Approach To Diabetes Mellitus Definitions

DCCT Diabetes Control and Complications Trial, a large, prospective, randomized controlled study of the advantages and disadvantages of tight versus loose diabetic control in type 1 diabetes. UKPDS United Kingdom Prospective Diabetes Study, a large, prospective. randomized controlled study of interventions and outcomes in type 2 diabetes. Diabetes mellitus is a general term for several different diseases that result in high blood sugar levels and that eventually lead to microvascular and macro vascular complications. The major classifications of diabetes mellitus are type I diabetes, type 2 diabetes, and gestational diabetes. Type 1 diabetes (previously called juvenile diabetes, juvenile-onset diabetes mellitus JODM or insulin-dependent diabetes mellitus IDDM ) results from destruction of insulin-producing pancreatic 3 cells. This destruction was previous thought to be viral related and to occur acutely. Recent studies indicate that there may be islet-cell antibodies present for years...

Annexins And Diabetes

Diabetes is a chronic condition that can present in two different ways type-1 insulin-dependent diabetes or the more common type-2 insulin non-dependent diabetes. In both instances it is the resulting hyperglycemia that is thought to be primarily responsible for the disease facies. Although diabetes is a systemic condition that affects all parts of the body, for the purposes of this discussion the endothelium will be the main point of focus, since the most complete data regarding the role of annexins in diabetes have come from studies examining their actions in endothelial cells. There are thought to be four major effects of hyperglycemia on endothelial cells an increase in flux through the polyol pathway which leads to a depletion of NADPH and ultimately diminishes the cell's ability to produce protective anti-oxidants, an increase in conversion of glucosamine-6-phosphate to N-acetylglucosamine which leads to the formation of transcription factor-sugar adducts (which can affect...

See also Action of Insulin from Chapter 23 Gluconeogenesis Control of Fatty Acid Synthesis Hormonal Regulation of Fuel

For PEPCK to function in gluconeogenesis, oxaloacetate produced in the pyruvate carboxylase reaction in the mitochondria, must be transported to the cytoplasm. PEPCK is not under any known allosteric control. Activity of the enzyme is regulated by hormonal control of its transcription. Glucagon stimulates transcription of the structural gene for PEPCK. Insulin inhibits transcription of the enzyme. By inhibiting PEPCK gene transcription, insulin tends to depress gluconeogenesis rates.

Diabetes and Sexual Dysfunction

A clear physiological association between diabetes and male sexual dysfunction is well established. In a comprehensive review of the literature, Eretekin (1998) found ample research evidence for chronic progressive impotence directly related to diabetes mellitus. It is either neuropathic or vascular, or both. In some instances impotence may lead to the discovery of the disease. Another rare sexual dysfunction affecting 1 to 2 of diabetic men is retrograde ejaculation. However, some researchers have suggested that this problem may be more common than generally believed. Psychological factors, which until recent times were seen as critical in the explanation of sexual problems associated with diabetes, have lost considerable ground as physical explanations have emerged. Another study found confirmation for the physical causes for sexual problems in diabetic men (Schiavi et al., 1995). Compared to healthy controls, diabetic patients had significantly lower levels of erotic drive, sexual...

Inulin and Diabetes Mellitus

Diabetes mellitus is a disease in which blood sugar is not properly taken up into cells. Thus, the level of glucose in the blood remains high. The uptake of glucose into the body's cells is controlled by the hormone insulin, which is produced by the pancreas. Type 1 diabetes is due to the pancreas failing to produce sufficient insulin. It is often caused by genetic factors. Non-insulin-dependent diabetes, or type 2 diabetes, occurs when the body's cells are unable to respond very efficiently to the insulin produced. It is associated with obesity, overnutrition, excess dietary fat and sugar, and other factors. Type 2 diabetes accounts for around 90 of all diabetes. Both types of diabetes are treated by the injection of insulin, which acts to reduce the blood glucose concentration by facilitating the uptake of glucose by the cells in type 1 diabetes, and by supplementing the body's insulin in type 2 diabetes. Over 18 million adults in the U.S. have diabetes (CDC, 2006), and over 170...

Acquired Generalised Lipodystrophy Lipoatrophic Diabetes or Lawrence Syndrome

Lipo Dostrophy Images

Acquired generalised lipodystrophy (AGLD) is a rare, juvenile-onset lipodystrophy, first fully described by Lawrence in 1946 1 , who reported on a young female subject with 'lipodystrophy, and hepatomegaly with diabetes, lipaemia and other metabolic disturbances.' To date, approximately 80 patients with AGLD have been reported 2 . Like others LDs, AGLD is prevalent in females. Lipoatrophy develops over a number of years, in childhood or in adolescence, so that the onset of the condition is later than that of congenital generalised lipodystrophy (CGLD). Extended areas of subcutaneous fat are involved, including the face, arms, and legs. Less frequently mesenteric, retroperitoneal, perirenal and mediastinal fat depots are involved, while retroorbital fat seems to be spared. Muscle mass, evaluated by dual energy X-ray analysis (DEXA), is preserved or even increased compared to age-, sex- and body mass index (BMI)-matched subjects. Therefore, in spite of the generalised atrophy of fat...

Monitoring Glycemic Control In Diabetic Patients

Our research with Hb variants clearly indicated that the same cIEF methodology used for the analysis of structural Hb variants could also be used for the analysis of posttranslational or chemically modified Hb variants. Post-translational hemoglobins include oxidation products (8) like methemoglo-bins and Hb A3 (glutathione adduct), and glycation products like Hb A1c. Adding additional tests to an existing platform and reagent system is attractive because of the potential for decreasing the instrument cost per test. Oxidation products, however, are only measured in a small number of specialized laboratories to help diagnose congenital methemoglobinemias, a class of disorders resulting in the oxidation of heme iron and decreased heme oxygen binding (2,4). However, many laboratories, including ours, measure Hb A1c as an indicator of the long-term glucose control in diabetic patients. The following is an initial report of our research and development of cIEF for the analysis of Hb A1c...

Pharmacotherapy for Weight Management and Prevention of Diabetes

Weight reduction for the prevention of cardiovascular disease is an imperative in the current environment of epidemic obesity and metabolic syndrome. However, the failure rate is 70-95 within 1-2 years of weight loss. Weight loss is followed by a number of adaptations including decreased thyroid and immune function and changes in signaling in the central nervous system that result in weight regain. Thus, the treatment of obesity, which is the common denominator underlying the variable symptoms of the metabolic syndrome, remains a challenge in cardiovascular rehabilitation and prevention. Programs should emphasize a moderate weight loss of 5-10 that is achievable by lifestyle change, rather than dieting, and that is maintainable over time. Drugs may assist with this goal,but no studies that demonstrate a reduction in cardiovascular morbidity or mortality as a result of drug-assisted weight reduction have been done. Promisingly, treatment with a number of drugs may reduce the incidence...

See also Hormone Action Hormone Mechanisms of Action Hormone Hierarchy of Action Receptors with Protein Kinase Activity

Protein Kinase Cancer Therapies Picture

The insulin receptor (Figure 23. ) is a glycoprotein with an ot2. 2 tetrameric structure, stabilized by disulfide bonds. Both the ot chain (735 residues) and the fi chain (620 residues) are translated from a single mRNA, giving a polypeptide chain that then undergoes proteolytic processing. The ot chain, which is thought not to span the membrane, is believed to bind insulin near its C-terminus. The fl chain has a transmembrane domain, with its C-terminus in the cell interior. The C-terminal region of the fl chain is the site of a protein tyrosine kinase activity, which is stimulated by the binding of insulin to the extracellular part of the receptor. The kinase activity of insulin receptor is essential to its biological activity, because some cases of non-insulin-dependent diabetes are associated with receptor mutations that abolish the kinase activity.

Carotenoids and the Insulin Like Growth Factor System

The identification of risk factors for various types of cancer can lead to appropriate preventive measures. The importance of the sex steroids estradiol and testosterone for the development and progression of breast and prostate cancers, respectively, is well known. Recently, a similar role has been proposed for insulin-like growth factor-I (IGF-I). Chan et al. (102) found a strong positive association between IGF-I levels and prostate cancer risk in participants of the Physicians' Health Study. An equally strong association between the level of this growth factor and breast cancer risk of premenopausal women was also reported in a case control study within the Nurses' Health Study cohort (103) and, more recently, for colorectal cancer (104). Thus, plasma IGF-I levels may be useful for The IGF system is composed of several components. IGF-I and IGF-II are related peptides and are among the most active growth factors in various types of cancer, including breast cancer (106). The IGF...

Criteria For Diagnosis Of Diabetes Mellitus

Symptoms of diabetes plus casual glucose concentration > 200 mg dL (11.1 mmol L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydispsia, and unexplained weight loss. FPG fasting plasma glucose OGTT oral glucose tolerance test 2hPG 2-hour plasma glucose. From Powers AC. Diabetes mellitus. In Braunwald E. Fauci AS. Kasper KL. et al. eds. Harrison's principles of internal medicine. 16th ed. New York McGraw-Hill. 2005 2153. macrovascular complications is seen at a fasting glucose > 110 mg dL. Once diabetes is diagnosed, therapy is instituted with three major goals. The foundation of diabetes therapy is dietary and lifestyle modifications. Randomized trials show that even small amounts of weight loss can lower blood pressure and improve glucose control. Patients should be given instruction in nutrition and encouraged to change sedentary lifestyles. Exercise that the patient finds enjoyable and...

Glucose Dependent Insulin Secretion

Insulin is secreted from -cells in the pancreas in an oscillatory fashion. Glucose must be metabolized by the -cell to stimulate insulin secretion, and the insulin, which is Figure 4.4 Flow system for experimental study of insulin secretion. Vbed is the volume of the reaction bed, f is the volume flow rate, and Go is the inflow concentration of glucose. Redrawn from Maki and Keizer, 1995 . prepackaged in secretory vesicles, is secreted from the -cell into the capillary system by exocytosis. However, the secreted insulin affects the transport of glucose into the cell by activating GLUT1 transporters and inactivating GLUT2 transporters. Thus, there is both positive and negative feedback, necessary ingredients for sustained oscillations. These oscillations have been studied experimentally in a flow system depicted in Figure 4.4. A thin layer of insulin-secreting -cells is sandwiched between beads and exposed to a steady flow of solution. By collecting the solution exiting the bed, one...

Notes For Prescribing Insulin

There is no need to change a stabilised diabetic from animal to human insulin. Unexplained requirement of above 100 units d is usually due to noncompliance and less often to antibodies since the withdrawal of the older insulin preparations. Allergy still occurs to additives (protamine), to the preservative, e.g. phenol, cresol, or to insulin itself. It may take the form of local reactions (inflammatory or fat atrophy) or of insulin resistance. Antibodies to insulin, provided they are moderate in amount, may be actually advantageous. They act as a carrier or store, binding insulin after injection and releasing it slowly as the free insulin in the plasma declines. In this way they smooth and prolong insulin action. But too high antibody concentrations cause insulin resistance. 4 An adverse effect of easy self-monitoring is that a minority of obsessional patients, told of the desirability of blood glucose concentrations being kept in the normal range to prevent diabetic complications,...

Using E coli to make insulin

It helps move sugars and starches from the bloodstream into the cells, where they can be used for energy. People who have a disease called diabetes either do not make enough insulin or do not use it properly. They need to take insulin every day to keep their blood sugar levels under control. In the past, people with diabetes were often given insulin that was taken from animals. But sometimes their immune systems would recognize this insulin as foreign, leading to an immune reaction. In the late 1970s, scientists began using E. coli to produce insulin. The bacteria can produce recombinant insulin in large amounts. Because recombinant insulin is identical to human insulin, it does not cause an immune reaction in people who take it.

Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

Overabundance of plasma triglycerides and free fatty acids entering the circulation by lipol-ysis from adipose tissue or by ingestion from food is frequently associated with pathophys-iology of insulin resistance and diabetes mellitus (Defronzo 2004). Results of radioactive tracer and stable isotope dilution studies have suggested that both hepatic and peripheral muscle tissues are involved in the development of insulin resistance (Defronzo 1988). Focusing on glucose uptake in skeletal muscle, based on the results of his experimental studies series, Sir Randle (Randle et al. 1963) postulated the hypothesis that the substrate competition for mitochondrial oxidation is the major mechanism involved in the impairment of glucose uptake into skeletal muscle. Recent studies applying 13C and 31P MRS methods (reviewed in Chapter 11 of this book) and analysis of skeletal muscle biopsy have shown that direct impairment of insulin signalling cascade (Griffin et al. 1999), and therefore direct...

Approach To Suspected Diabetes Mellitus Definitions

Type I diabetes Caused by what is believed to be an autoimmune destruction of the pancreatic beta cells and complete loss of endogenous insulin production. The presentation of this type of diabetes usually is acute, with hyperglycemia and metabolic acidosis. These patients are dependent upon exogenous insulin delivery. Type 2 diabetes Heterogenous syndrome of insulin resistance caused by genetic factors and or obesity and relative insulin deficiency. Oral medications to enhance endogenous insulin production or improve insulin sensitivity are useful. Exogenous insulin may be used when oral medications are no longer sufficient for adequate glycemic control. As the prevalence of obesity increases in the American population, so does the prevalence of type 2 diabetes, especially in children and teenagers. Ninety percent of all new cases of diabetes diagnosed in the United States are type 2, and it is estimated that this disease affects approximately 7 of the population older than 45 years....

Special Considerations for Type 1 Diabetes

Nutrition recommendations for a healthy lifestyle for the general public14 are also appropriate for persons with type 1 diabetes. Since the body weight of patients with type 1 diabetes is usually normal, energy intake does not have to be modified. Many type 1 diabetic patients are now treated with intensive insulin therapy (insulin pumps or basal-bolus insulin regimen). For these patients, the total carbohydrate content of meals (and snacks) is the major determinant of the premeal insulin dose and the postprandial glucose response. Thus, patients treated with intensive insulin therapy are advised to adapt the premeal insulin dose to the carbohydrate content of the meal. For planned exercise, reduction in insulin dosage may be the preferred choice to prevent hypoglycemia. Additional carbohydrate may be needed for unplanned exercise. For instance, a 70 kg person would need between 10 and 15 g carbohydrate per hour of moderate physical activity.

Regulation of endogenous glucose output during euglycaemic hyperinsulinaemia

Of insulin and glucagon (Cherrington 1999). Although irrelevant during a hyperinsulinaemic clamp test performed at euglycaemia, hyperglycaemia per se also exerts a powerful inhibitory effect on endogenous glucose output (Bell etal. 1986). Because glucoregulatory hormones other than insulin, such as glucagon, are only gradually suppressed during hyperinsulinaemic euglycaemic clamp tests (Prager etal. 1987 Lewis etal. 1998), two other factors essentially impact on endogenous glucose output. These factors are the degree of hyperinsulinaemia per se and the insulin sensitivity of hepatic glucose output. Since insulin is physiologically secreted into the splanchnic circulation, portal vein plasma concentrations of insulin exceed those in peripheral and arterial plasma. The physiological range of the ratio between portal venous and peripheral venous insulin concentrations is approximately 2-2.5 1 (Waldhausl etal. 1982). During a clamp experiment, endogenous insulin secretion can be monitored...

Preparation of the insulin infusion

The insulin infusate is prepared with human insulin, which is added to isotonic saline. The insulin infusion pump must be calibrated and must provide sufficient fine gears to allow the administration of the calculated insulin dose. In order to prevent the absorption of the hormone in plastic surfaces, 2 ml of the individual's blood per 48 ml of the infusate is added to the infusate (Sherwin etal. 1974 DeFronzo etal. 1979). The effectiveness of this method can be proven by measuring the insulin recovery in the infusate after it is pumped through the infusion lines (Sherwin etal. 1974 Insel etal. 1975 DeFronzo etal. 1979). This may be of special interest when clamp experiments are performed with investigative apparatus such as nuclear magnetic resonance spectrometers or positron emission tomography, which complicate the use of infusion pumps with short infusion lines.

Application of muscle biopsy in diabetes

Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes (Beck-Nielsen & Groop 1994 Beck-Nielsen 1998 Beck-Nielsen et al. 2003). During the past two decades, skeletal muscle biopsies have been increasingly applied in the search for biochemical and molecular abnormalities responsible for insulin resistance. It is evident that type 2 diabetes is caused by a complex interplay between genetic and environmental factors. The latter include intrauterine malnutrition and postnatal factors such as obesity, physical inactivity and modern Western lifestyle, as well as the metabolic milieu associated with type 2 diabetes and prediabetes, including glucose intolerance, hyperglycaemia, hyperlipidaemia and hyperinsulinaemia (Beck-Nielsen & Groop 1994 Beck-Nielsen 1998 Beck-Nielsen et al. 2003). The choice of study design is therefore extremely important for the interpretation of data obtained (Table 14.1). Novel potential markers of insulin resistance and type 2 diabetes...

Changing the Fate of Diabetics in the Dialysis Unit

In a symposium on diseases of kidney reported in 1971 Williem J. Kolff was quoted as saying in 1938, 'Gradually the idea grew in me that if we could only remove 20 g of urea and other retention products per day we might relieve this man's nausea and that if we did this from day to day, life might still be possible' 8 . Dunea 8 started his article after this statement and wrote, 'Within three decades dialysis has revolutionized the field of nephrology and opened new vistas in the treatment of uremia. Yet, dialysis gradually outgrew its difficult beginnings and became established among the great medical achievements of our age.' In this article there is no mention of the diabetic ESRD patient. A year later in 1972, Ghavamian et al. 9 report on 9 patients with renal failure resulting from DN who were treated by hemodialysis. The average duration of diabetes was 21 years and the average duration of nephropathy was 26 months. One patient survived for more than 3 years. The others survived...

Insulin stimulated whole body glucose metabolism

During euglycaemic hyperinsulinaemia, skeletal muscle is primarily responsible for the insulin dependent increase of whole body glucose metabolism (Figure 4.4 and 4.6A) DeFronzo etal. 1985). The contribution of the liver to whole body glucose metabolism is small under these conditions. However, splanchnic glucose uptake and thus the contribution of the liver to whole body glucose metabolism increases under hyperglycaemic hyperin-sulinaemic conditions (Basu et al. 2004 Krssak et al. 2004). Insulin stimulated whole body glucose metabolism depends on two major metabolic pathways glucose oxidation and nonox-idative glucose metabolism. Nonoxidative glucose metabolism is primarily represented by glycogen synthesis, and skeletal muscle is the tissue accounting for the majority of insulin stimulated glycogen synthesis (Shulman etal. 1990). In insulin resistant states, lower rates of skeletal muscle glycogen synthesis are responsible for the reduction of insulin stimulated whole body glucose...

Diabetes Insipidus

Diabetes insipidus is a rare complication of AML.57 Patients present with polyuria, polydipsia, and a low-serum antidiuretic hormone (ADH) level.58 Cytogenetic abnormalities associated with cases in the literature include monosomy 7, deletions of chromosome 7, and chromosome 3 abnormalities.5759 The reason for these specific associations is unknown.57 However, the proposed mechanism involves leukemic infiltration of the neurohypophysis. Magnetic resonance imaging (MRI) demonstrates a bright spot in the neurohypophysis prior to treatment.59 Both MRI findings and ADH release subsequently resolve after chemotherapy.59

Insulin infusion

The goal of the insulin infusion is to acutely raise and maintain the plasma insulin concentration at a new hyperinsulinaemic plateau for the duration of the clamp experiment. The insulin infusion rate applied depends on the desired steady state plasma insulin concentration during the clamp. In the original experiments reported by Sherwin etal. (1974) and De Fronzo etal. (1979), plasma insulin concentrations were raised to approximately 100 U ml above fasting levels by applying a continuous insulin infusion rate of 1 mU per kg bodyweight per minute or 40 mU-per square metre body surface area per minute, respectively. Since then, various insulin infusion rates have been applied during glucose clamp tests. However, one should be aware that when plasma insulin concentrations are raised above 500 U ml (corresponding to an insulin infusion rate of 200 mU-m-2-min-1), the physiological clearance mechanism of plasma insulin is saturated and plasma insulin concentrations will continuously...

Insulin and IGFs

Insulin Several of the mitogenic actions previously ascribed to insulin may be due to IGF contamination of the original preparations. Insulin is quite unstable at 37 C (particularly in media with high levels of cysteines) with > 90 of its activity being destroyed over 1 hr (87). It is often added to media at relatively high concentrations and because insulin has a weak affinity for IGF-1 receptors, it may activate the same mitogenic responses as IGF-1 at these high doses. However, insulin is also added to most serum-free media for its ability to promote energy and anabolic metabolism (e.g., glucose uptake and oxidation, synthesis of glycogen, amino acid transport) (75). The ubiquitous insulin receptor is a dimer that has tyrosine kinase activity (88). Insulin requires adequate zinc to exert its biological function and should be present in the culture medium. Insulin-Like Growth Factors These peptides are homologous to insulin and evolved by gene duplication (89). They were first...

Diabetes Mellitus

Patients with diabetes have an increased incidence of CHD, hypertension, and heart failure (203,204), which is in part induced by the metabolic and structural changes seen in the diabetic heart. The diabetes-induced structural changes in the myocardium consist of increased fibrosis and increased ventricular mass (205,206), conditions that together with the more aggressive atherosclerosis may explain the higher cardiac morbidity and mortality in patients with diabetes. Both type 1 and 2 diabetes have been associated with increased levels of natriuretic peptides (207-210). Contrasting population-based data suggest that diabetes is associated with lower natriuretic peptide concentration (108), independent ofthe effect of obesity (108). However, in experimental animal models, diabetes increases the expression of cardiac BNP (211) and prevents myocardial growth via a cGMP-dependent mechanism (212). In humans, acute (i.e., lasting for hours) hyper-insulinemia causes an increase in ANP, but...

Diabetes

Pregnancy reduces the ability of insulin to control blood sugar. Most pregnant women secrete more insulin to balance this effect, and glucose control remains normal. However, about 5 of pregnant women develop glucose intolerance or diabetes.16 Diabetes during pregnancy can harm both the mother and fetus and increase risk for complications during delivery. Because diabetes can develop without visible symptoms, all women should be screened midway through pregnancy. Nutrition and moderate exercise are the cornerstones of the prevention and treatment of diabetes during pregnancy. Eating small, frequent meals high in complex carbohydrate and fiber can help control blood sugar. Moderate exercise can enhance the action of insulin, along with supplemental zinc and chro-mium.16 In over 95 of women, diabetes during pregnancy disappears after delivery.

Diet Diabetes

The best way to prevent type 2 diabetes is to avoid gaining weight. Overweight people are four times more likely to develop type 2 diabetes than those who maintain normal body weight. Overweight diabetic patients can often reduce their need for drugs and control their blood sugar by weight loss. The glucose tolerance factor (GTF) is a naturally occuring compound that helps regulate blood sugar. It is found in rich amounts in brewer's yeast. Chromium is an essential component of GTF, and diets deficient in chromium produce glucose intolerance (see Fig. 5.11 ).1-3 Diabetics who excrete glucose in their urine have increased urinary loss of minerals (such as magnesium, zinc, and chro mium). Deficiencies of these important minerals further impair the ability to control blood glucose. Therefore, diabetic diets should emphasize foods rich in these minerals. The best diet for most diabetics is one low in refined sugars and high in complex carbohydrates and fiber (which slow absorption of...

Insulin

Soon after insulin was isolated it was found to help support growth of cells in culture.188 The idea that insulin might be a growth-stimulatory factor was supported by the observation that many of the mitogenic peptides derived from blood have an insulin-like activity. Whether insulin has a physiologically important mitogenic activity in vivo, however, is questionable, because supraphysiologic concentrations of insulin are usually needed to stimulate cell proliferation and the mitogenic effect is usually small compared with that of total serum or other mitogenic peptides.189 Insulin, however, frequently acts synergistically with other growth factors, probably because it is required for optimal uptake and utilization of needed nutrients. Characterization of the cell surface receptor for insulin has led to a broader understanding of how insulin and insulinlike factors work. The insulin receptor is a tetrameric disulfide-linked complex containing two a subunits of 125,000 MW and two p...

Sources of insulin

Insulin is synthesised and stored (bound to zinc) in granules in the p-islet cells of the pancreas. Daily secretion amounts to 30-40 units, which is about 25 of total pancreatic insulin content. The principal factor that evokes insulin secretion is a high blood glucose concentration. Insulin is a polypeptide with two peptide chains (A chain, 21 amino acids and B chain, 30) linked by two disulphide bridges. The basic structure having metabolic activity is common to all mammalian species but there are minor species differences, which result in the development of antibodies in all patients treated with animal insulins, as well as to unavoidable impurities in the preparations, minimal though these now are. Bovine insulin differs from human insulin by three amino acids and is more antigenic to man than is Porcine insulin differs from human by only one amino acid Human insulin (1980) is made either by enzyme modification of porcine insulin, or by using recombinant DNA to synthesise the...

Insulin receptors

Insulin binds to the a subunit of its receptor. The p subunit is a tyrosine kinase which is activated by insulin binding and is autophosphorylated. Tyrosine kinase also phosphorylates other substrates so that a signalling cascade is initiated and biological response ensues. Insulin receptors are present on the surface of the target cells (mostly liver, muscle, fat). Receptors vary in number inversely with the insulin concentration to which they are exposed, i.e. with high insulin concentration the number of receptors declines (doivn-regulatiori) and responsiveness to insulin also declines (insulin resistance) with low insulin concentration the number of receptors increases (up-regulation) and responsiveness to insulin increases. Type 2 diabetes patients have insulin resistance. Hyperinsulinaemia predates the onset of diabetes and the resistance is thought to be secondary to down-regulation of insulin receptors as well as postreceptor, intracellular events. Obesity is a major factor in...

Actions of insulin

The effects of stimulation of the insulin receptors include activation of glucokinase and glucose phosphatase. Insulin also increases glucose transport Other metabolic effects. In addition to enabling glucose to pass across cell membranes, the transit of amino acids and potassium into the cell is enhanced. Insulin regulates carbohydrate utilisation and energy production. It enhances protein synthesis. It inhibits breakdown of fats (lipolysis). An insulin-deficient diabetic (Type 1) becomes dehydrated due to osmotic diuresis, and is ketotic because fats break down faster than the ketoacid metabolites can be metabolised.

Insulin nomenclature

The problems have arisen because insulin is a naturally occuring molecule (differing slightly among species), which has been formulated in many ways partly catering for differing patient requirements, and partly reflecting a variety of manufacturing processes used by pharmaceutical companies. Fortunately, there has been considerable rationalisation of the preparations but it may be helpful to explain some remaining ambiguities. Soluble and neutral insulin are the same the British National Formulary favours the former term, but neutral is the INN (internationally approved) name, dating back to when there were acid and neutral pH formulations of soluble insulin. Human, porcine and beef are available. Isophane insulin is the only approved name for suspensions of insulin with protamine. Human, porcine and beef are available the latter is rarely used. Biphasic insulins are, with one exception, proprietary mixtures of soluble (neutral) insulin and isophane...

Antidiabetic Drugs

Cannabis increases appetite and so when taken regularly it may appear to reduce the effectiveness of antidiabetic medication by increasing carbohydrate intake. By contrast, a case of diabetic ketoacidosis supposedly caused by oral administration of cannabis has been described (Hughes et al., 1970). The patient exhibited the classic signs and symptoms of diabetic coma within 24 hours of eating an unspecified quantity of cannabis. The link with cannabis is exceedingly tenuous for the following reasons he had a family history of diabetes he had smoked cannabis before on numerous occasions without problems and he was still frankly diabetic, requiring insulin, one month after this event. The temporal link between florid symptoms of diabetes and the ingestion of cannabis was undoubtedly coincidental.

The insulin infusate

Where insulin is to be infused over prolonged periods, it is important to be sure that the concentration of the infusate remains stable. The dose is often estimated in milliunits of insulin per kilogram body weight, although using the body surface area is preferable, especially where subjects of different sizes are to be compared. Body surface area relates more precisely to volume of distribution. The specific requirements for individual studies are discussed below. Insulin sticks to plastic and so an insulin infusate will lose strength over time. To avoid this it is usual to make the insulin up in a 4 solution of autologous blood, and it is critical that the insulin is mixed by slow rotation (to avoid bubbling). The solution is then run through the entire giving apparatus, to saturate the binding sites in the plastic from the beginning. For infusions lasting more than five hours, fresh solutions should be made. A small amount of all infusions should be kept for later estimation of...

Molecular Mechanisms of Transdifferentiation

Foxo2 is a gene for a transcription factor expressed exclusively in adipose tissue. Its overexpression in the adipose tissue of transgenic mice gives rise to an obesity-resistant and more insulinsensitive lean phenotype. These mice show a transformation of white into brown adipocytes 72 . Interestingly, individuals with greater insulin resistance exhibit a reduction of FOXO2 (human foxo2) in subcutaneous abdominal fat accompanied by down-regulation of other genes of the brown adipocytic phenotype.

Phosphatase and Tensin Homologue

PTEN also inhibits signaling from the insulin growth factor receptor (IGF-R). Insulin receptor substrates-112 (IRS-1 2) are docking proteins that are recruited by the insulin receptor and in turn, recruit PI-3K for signal transduction. The tumor suppressor function of PTEN helps to prevent aberrant signaling when insulin binds to its cell surface receptor.

Solid Phase Organic Synthesis Of Informational Macromolecules Of Interest To Medicinal Chemists

An added feature to bear in mind is that the preparation of certain medically important polypeptide drugs, such as human insulin and growth hormone, through genetic engineering methodologies, is well developed and convenient so these substances can be used in parenteral replacement therapy. Their preparation through synthetic peptide chemistry represents important achievements in peptide intellectual technology but does not satisfy a commercial need.

Components of the PSD

Fig. 1 Schematic diagram of PSD proteins. Examples of PSD proteins are shown along with their domain structures. PDZ domains are shown as gray ellipses. Other domains are indicated Actl, actin regulatory domain 1 Act2, actin regulatory domain 2 AD, association domain Ank, ankyrin repeats ArfGAP, Arf GTPase-activating protein C2, calcium lipid binding domain 2 CAM kinase, Ca2+ calmodulin-dependent kinase (CAME)-like domain CC, coiled coil domain CRIB, Cdc42 Rac-interactive binding EVH1, ENA VASP homology domain 1 GH1, GKAP homology domain 1 GK, guanylate kinase-like domain GKBD, PSD-95 GK binding domain GRKBD, GRK2 binding domain Kinase, serine threonine kinase domain L27, domain initially found in LIN2 and LIN7 PDZ, PSD-95 Dlg ZO-l domain LRR, leucine rich repeat PH, pleckstrin homology domain RapGAP, Rap GTPase-activating protein RasGAP, Ras GTPase-activating protein RCB, Rac binding domain SAM, sterile a motif SH3, Src homology 3 domain SHD, Spa2 homology domain WW, domain with two...

Regulatory Considerations for the Chromatographer

A good specification is one that provides for material balance. The sum of the assay results plus the limits tests should account for 100 of the drug within the limits of accuracy and precision for the tests. Limits should be set no higher than the level which can be justified by safety data and no lower than the level achievable by the manufacturing process and analytical variation. Acceptable limits are often set for individual impurities and for the total amount of drug-related impurities. Limits should be established for by-products of the synthesis arising from side reactions, impurities in starting materials, isomerization, enantiomeric impurities, degradation products, residual solvents, and inorganic impurities. Drugs derived from bio-technological processes must also be tested for the components with which the drug has come in contact, such as the culture media proteins (albumin, transferrin, and insulin) and other additives such as testosterone. This is in addition to all...

Csaba Szabo and Solomon H Snyder

Poly(ADP-ribose) polymerase (PARP), also termed poly(ADP-ribose) synthetase (PARS), is a nuclear enzyme with a wide range of functions including regulation of DNA repair, cell differentiation, and gene expression.1,2 More than a decade after the identification of PARP-like enzymatic activities in mammalian cells, Dr. Nathan Berger and colleagues3,4 proposed a novel role for this enzyme, mediating a suicidal mechanism triggered by DNA strand breakage. As summarized in 1995 by Berger, when DNA strand breaks are extensive or when breaks fail to be repaired, the stimulus for activation of poly(ADP-ribose) persists and the activated enzyme is capable of totally consuming cellular pools of NAD. Depletion of NAD and consequent lowering of cellular ATP pools, due to activation of poly(ADP-ribose) poly-merase, may account for rapid cell death before DNA repair takes place and before the genetic effects of DNA damage become manifest. 5 This hypothesis has since become a controversial...

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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