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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. You will learn the real root causes of this condition, truth about germs, and how to improve the quality of our cells with a lot of useful nutrition tips. Finally, what people will learn, of course, is a concrete treating plan for diabetes that helps to kick the disease out of your body once and for all. In fact, this treatment is very simple, but it can stop your anxiety about diabetes effectively and fast! 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. More here...

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Section F Diabetes Chapter

Endothelins and Microvascular Endothelial Responses in Diabetes 671 Mechanism of ET Alteration in Diabetes ETs and Microcirculatory Flow Alterations Endothelins in Microvascular Endothelial Dysfunction Endothelins in Organ-Specific Microvascular Alterations in Diabetes Concluding Remarks Von Willebrand Factor Diabetes and Endothelial Dysfunction 683

Availability of Insulin

Unfortunately insulin, even in standard formulations (porcine, bovine or human insulin in vials for subcutaneous injections), is not necessarily accessible to all patients with type 1 diabetes. In a survey by the International Diabetes Federation (IDF) Task Force on Insulin performed in 2003 1 , only 44 and 40 out of 74 responding countries reported uninterrupted access to insulin for people with type 1 or type 2 diabetes, respectively. Thus, in 30 countries, people with type 1 diabetes were without continuous access to insulin. Cost remains a major cause of lack of access. However, availability, transportation problems and poor quality of insulin were also reported as major issues. There are considerable regional differences with African countries reporting the worst situation. An unfortunate consequence of low access to insulin is pressure on health personnel and authorities to give preference to people with type 1 diabetes over people with type 2 diabetes. However, as highlighted...

Provision Of Services In Diabetes Care

In 1997, Diabetes UK, formerly the British Diabetic Association, investigated the provision of dietetic services in diabetes care. They carried out a postal survey to dietitians in the UK to assess level of provision and current practices including application of nutritional guidelines, audit and evaluation. The survey showed that 85 of dietitians worked in situations where dietetic provision was less than the current recommendation of 22.5 hours per 100000 of the population, made by Diabetes UK, in 1999 (18). One of the outcomes of this situation is that people with diabetes may not receive dietary education from a State Registered Dietitian. Dietary education may be part of an education package offered in general practice by the practice nurse. The evolution of the nutritional guidelines for people with diabetes to a status which is in line with healthy eating recommendations for the general population may have 'de-mystified' the diet in diabetes care to the extent that it was...

The Global Insulin Market

Sales of rapid-acting analogues of insulin now exceed those for human sequence insulin. Humalog and Novolog (Novorapid) had combined sales totalling US 1555.2 million in 2005 compared with US 870.2 million for all other rapid-acting insulins, Humalog being the market leader. The intermediate-acting insulins, Humulin and Novolin (Insulatard) being the dominant examples, sold US 1050.8 million in 2005, which was a small decrease compared with 2004. The market (US 1576.8 million in 2005) for prolonged-duration analogues is dominated by Lantus, with Levemir gaining some ground since its introduction. All insulins, including premixed formulations with a sale of US 2256.1 million in 2005 and dominated by Novolog Mix, Novolin Mix and Humalog Mix, are used for both type 1 and type 2 diabetes (all data from 5 ). As a consequence there has been a general increase in the use of insulin. Data from recent years in Denmark (with an estimated 25,000 patients with type 1 diabetes and more than...

Prescribing of Insulin in Type 1 Diabetes

Internationally, guidelines for the treatment of type 1 diabetes vary little between countries. In essence, the goal remains near-normal glucose levels without inducing severe hypoglycaemia. The options available are legion although the intrinsic limitations of subcutaneous insulin delivery continue to act as a barrier to attainment of this goal in the majority of patients. Although some regimens appear to offer certain advantages over others 7 , the choice of treatment remains dependent on the availability of insulin preparations (and delivery systems), local professional expertise and provision of support, and individual preferences of both patients and the diabetes healthcare team. As stated above, while paradigms of care may change, the choice of therapy often reflects the impact of factors other than evidence for treatment efficacy (and safety). For example, in otherwise comparable markets (Denmark and Sweden), the use of continuous subcutaneous infusion systems varies...

The Market for Antidiabetic Agents for Type 2 Diabetes

Including insulin, half of the global diabetes market is accounted for by the USA. Other major markets are Germany (7 ), the UK (4 ) and France (3 ). Highly populated countries with substantial numbers of people with diabetes such as Russia and Brazil each account for approximately 1 of the market. The market is dominated by (54 ) original branded drugs however, generics account for some of the market and unknown numbers of patients are treated with generics in countries such as China and India where licensing regulations are less strict 5 . Oral antidiabetic drugs account for 58 of the total market worth US 18.6 billion in 2005, an increase of 11.5 compared with 2004. The market is led by the thiazolidinediones with a pioglitazone turn-over worth US 2.544 billion in 2005 (rosiglitazone US 2.258 billion, rosiglitazone metformin combination US 382.7 million, metformin US 518.7 million, glimepiride US 857.9 million, vogiblose US 547.1 million). There are few descriptions of regional...

Prescribing of Antidiabetic Drugs for Type 2 Diabetes

Although hard end-point studies are somewhat sparse in diabetology, little doubt exists that near-normal blood glucose levels are beneficial, relieving symptoms and preventing long-term vascular complications. Guidelines are legion, and treatment goals are becoming increasingly ambitious. For example, the latest IDF guidelines for the treatment of type 2 diabetes 10 aim for HbA1c levels lower than 6.5 . Since this goal is rarely achieved through lifestyle measures alone, oral antidiabetic agents are usually required. Initially, monotherapy is commenced with the most appropriate drug, based on the clinical and biochemical profile of the patient, and in the light of safety considerations. For most patients, drugs from different classes are required in varying combinations, insulin being ultimately necessary in many patients. Current guidelines recommend metformin and sulphonylureas as first-line therapy. Other regimens may be equally effective or even more so. However, comparative...

Redefining Diabetes What are the Consequences for Prognosis and Diagnostic Tests

Following the change in diagnostic threshold for diabetes by ADA in 1997, a large range of studies analysed the potential consequences of changing the diagnostic criteria for diabetes. The largest and most systematic effort was done through the DECODE-study initiated under the European Diabetes Epidemiology Study Group 12 . This collaborative effort used population-based epi-demiological studies of diabetes based on the use of a standard 75-g oral glucose tolerance test from a large number of centres in Europe to analyse the effect of revising the diagnostic criteria. Most of the publications are based on data from between 25,000 and up to 50,000 individuals. modifying the diagnostic criteria in 1999, where WHO in contrast to the ADA recommended the use of the oral glucose tolerance test in epidemiologi-cal surveys as well as in the diagnosis of diabetes in individuals at high risk based on the fasting plasma glucose. In conclusion, the revised diagnostic criteria for diabetes,...

Reclassifying Diabetes How to Differentiate Between Type 1 and Type 2 Diabetes

So far the focus on the 1997 ADA and 1999 WHO revision of the diagnostic criteria has been on the impact of the revised diagnostic thresholds. Another often neglected but equally (or even more) important revision relates to the classification of patients. In 1985, patients were classified as having insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes based on the underlying disease, that is, whether beta-cell dysfunction was reduced to a level where insulin was needed to survive without entering ketoacidosis (insulin-dependent diabetes) or whether the patient had diabetes based on insulin resistance (with or without associated beta-cell dysfunction) where the patient would survive without insulin, but where insulin could be necessary to maintain acceptable metabolic control. From 1985 and onwards several clinical studies 14 as well as practical clinical experience demonstrated that a large proportion of patients characterised as non-insulin dependent would subsequently...

Prevention Of Type 2 Diabetes

There is now unequivocal evidence that physically fit people are less likely to develop Type 2 diabetes and some intervention trials have shown that encouraging people with impaired glucose tolerance (IGT) to increase their physical activity significantly reduces their risk of developing diabetes (14-16). This benefit is independent of body mass index (BMI) and there is some evidence that physical activity has a greater protective effect as BMI increases (17). It may be of more importance for people at risk of Type 2 diabetes to increase their physical fitness rather than concentrate on weight reduction.

Exercise And Diabetes

Despite the widespread beliefs of the benefits of physical activity and the promotion of exercise by many health professionals, people with diabetes are reluctant to increase their physical activity (22). This is not restricted to those with diabetes as it applies to the British population as a whole. A UK study in 1990 showed that only 15-30 of British adults are taking sufficient exercise for optimum health and that there is a large discrepancy between people's perception of their fitness and the amount of exercise they actually take (23). A recent Canadian study has shown that while 84 of people with diabetes thought they should be exercising, only 45 were actually doing so (24). Against this background of reluctance to exercise there is also a lack of knowledge of the physiology of exercise. In order to maximise the advice given to people with diabetes who wish to increase their physical activity, it is essential to gain an understanding of the physiology of physical activity,...

Interventions Aimed at Improving Insulin Sensitivity

It is not possible within the confines of this chapter to discuss all possible therapeutic approaches to the abnormalities and clinical syndromes that comprise the IRS. For example, although type 2 diabetes is one of the clinical syndromes that occur more commonly in insulin-resistant individuals, guidelines outlining appropriate treatment are readily available, and need not be reviewed here. Instead an attempt will be made to selectively address issues considered to be of particular clinical relevance decisions for inclusion and exclusion that will clearly reflect the biases of the author. If insulin resistance compensatory hyperinsu-linemia play a primary role in the pathogenesis of the IRS, it seems obvious that increasing insulin sensitivity, and thereby also lowering circulating plasma insulin concentrations, should be the treatment of choice. Unfortunately, as should soon become apparent, the situation is not quite that simple. In this next section, an attempt will be made to...

With Type 1 Diabetes Mellitus

At the turn of the century a patient diagnosed with Type 1 diabetes mellitus had average life expectancy of only two years. The development of insulin as a therapeutic agent revolutionized the treatment of diabetes mellitus by changing it from a rapidly fatal disease into a chronic illness. Unfortunately this increased longevity brought to the fore serious secondary complications including nephropathy, neuropathy, retinopathy and macro- and microvascular complications in survivors 10 to 20 years after disease onset. The annual national direct and indirect costs of Type 1 and 2 diabetes in 2002 - including hospital and physician care, laboratory tests, pharmaceutical products, and patient workdays lost because of disability and premature death - exceeded 130 billion.1 Currently, the prevalence of Type 1 diabetes in the United States is estimated to be 1,000,000 individuals, and 30,000 new cases are diagnosed each year. Presently there is no practical mechanical insulin-delivery method...

The glycaemic index of foods and its effect on insulin response and glycaemia

The glycaemic response to a food, which in turn affects the insulin response, depends on the rate of gastric emptying, as well as on the rate of digestion and absorption of carbohydrates from the small intestine (Jenkins et al., 1987). Traditionally, carbohydrates were classified as 'simple' and 'complex' based on their degree of polymerization. Sugars (which are mono- and disaccharides) were therefore classified as simple, whereas starches (poly-saccharides) were classified as complex. However, carbohydrates might be better classified on the basis of their physiological effects, for example their ability to increase blood glucose. The glycaemic response depends both on the type of sugar (e.g. glucose, fructose, galactose) and the physical form of the carbohydrate (e.g. particle size, degree of polymerization) (Augustin et al., 2002). The GI is defined as the area under the glucose response curve after consumption of 50 g available carbohydrate from a test food divided by the area...

Diet Lifestyle and Diabetes Control

The value of diet and lifestyle change including the incidence of type-2 diabetes mellitus has been clearly demonstrated in three recent studies with Table 2. Coronary heart disease risk factors associated in type-2 diabetes mellitus 6 Raised insulin levels reductions of 30-50 in diabetes incidence in high-risk groups 24-26 . The Diabetes Prevention Program trial found that diet and lifestyle reduced the diabetes incidence by 58 and was more effective than metformin at 31 risk reduction 24 . Epidemiological studies, notably the Nurses Health Study, attributed 91 of the risk of type-2 diabetes to five major diet and lifestyle factors which included regular exercise, a body mass index of < 25kg m2, cereal fiber and consumption of low glycemic index diets 25 .

Importance of Glycemic Control in Diabetes

Based on the Diabetes Control and Complications Trial data in type-1 diabetes 27 , it was considered that improved glycemic control would help in the prevention of diabetes-associated complications 28 . This view has been confirmed by the results of the UK Prospective Diabetes Study in type-2 diabetes 19 . Loss of excess body weight continues to be a goal for patients with type-2 diabetes to improve blood glucose control and serum lipid profiles. Furthermore, in view of the threefold to fourfold increased risk of CHD that accompanies diabetes mellitus, additional strategies are sought to normalize a constellation of CHD risk factors (table 2), including serum lipids. Recently the American Diabetes Association (ADA) stated that the 'regulation of blood glucose to achieve near-normal levels is a primary goal in the management of diabetes, and, thus, dietary techniques that limit hyper-glycemia following a meal are likely important in limiting the complications of diabetes' 29 . The ADA...

Diabetes Prevention Program

The study 44 was initiated with two pharmacological treatment arms (metformin and troglitazone) however, the hepatic toxicity of troglitazone resulted in a premature closure of that portion of the study. As discussed above, although metformin is unlikely to act by increasing insulin-stimulated glucose disposal, it is often considered to be an insulin sensitizer. Be that as it may, the report of the diabetes prevention program (DPP 44 ) found that the administration of metformin, 850 mg, twice day, resulted in a 31 decrease in the incidence of type 2 diabetes during the average follow-up period of 2.8 years. Parenthetically, the life-style intervention of weight loss and increased physical activity led to a 58 decrease in the incidence of diabetes, and this intervention was statistically more effective than metformin. The results of metformin treatment arm are often viewed as evidence that diabetes was prevented. However, it is essential to distinguish between preventing type 2...

Diabetes In Children And Adolescents Not Due To Type 1 Diabetes

Type 2 Diabetes Non-insulin-dependent, non-immune-mediated Type 2 diabetes has always been considered rare in children. However, in Japan it is more common than Type 1 diabetes and has increased greatly in incidence in the last two decades (83). Also in recent years in certain paediatric populations in the USA Type 2 diabetes has accounted for up to 45 of newly diagnosed diabetes (9,10) and there is evidence that this type of diabetes is now on the increase in the UK (11). The highest risk groups for Type 2 diabetes in youth are obese, physically inactive, female adolescents with a family history of diabetes, particularly from ethnic minority communities (12,13). In adults, Type 2 diabetes is difficult to manage and there is a high reported incidence of serious vascular complications. Its emergence in adolescence is therefore a major public health concern, particularly as in this age group non-adherence in terms of clinic attendance and treatment regimens is common (7).

Diabetes Secondary To Chronic Diseases Of Childhood

Cystic Fibrosis (CF)-related Diabetes As life expectancy in CF improves, slowly evolving, non-ketotic, glucose intolerance and diabetes is becoming more frequent (14). The diabetes is predominantly due to insulin deficiency but there are elements of insulin resistance and, because of co-existing pancreatic exocrine deficiency, there is a need for high-energy, complex carbohydrate and high-fat foods which conflicts with the usual advice for diabetes in terms of cardiovascular risk. Moreover it is common practice in CF to use overnight gastrostomy feeds to improve nutrition and steroid therapy is often prescribed. Both of these increase glucose intolerance (and may initially precipitate diabetes). Alterations of food intake and absorption and constantly changing treatments demand flexibility in both nutrition education and insulin regimens, especially as the diagnosis of diabetes in addition to CF is particularly demoralising. Treated p-thalassaemia with chronic iron overload is...

Lactic Acid Insulin and Angiogenesis

We end this chapter with a brief discussion of the relationship between lactic acid, insulin, and angiogenesis in wound healing and cancer. As mentioned earlier, vascular cells proliferate and migrate toward an angiogenic stimulus, usually toward a low-oxygen (hypoxic) environment. In wound healing, hypoxia occurs from a lack of blood circulation in the traumatized area. In tumors, hypoxic conditions occur both through inflammation, which reduces blood flow, and the chaotic development of blood vessels within tumors. One growth factor that is intimately involved in glyco-lysis is insulin. Insulin stimulates not only glycolysis but also proliferation of many cancer cell lines.54,58-60 It glucose (blood sugar) enzymes may facilitate angiogenesis by increasing lactic acid production in hypoxic tumor cells and by stimulating the proliferation of vascular cells. For example, insulin injection can increase angiogenesis in mice.61 High insulin levels are common in cancerous tissue and in the...

GI and Diabetes Treatment and Prevention

Although different carbohydrates do produce differing glycemic responses, to be of benefit clinically, this benefit should translate into long-term improvements in glycemia or lipids. Table 2 summarizes the research comparing high versus low GI diets on glucose and lipid outcomes in studies with a minimum duration of 2 weeks 14-28 . Examining the data reveals no clear trend in outcome benefits. A meta-analysis of GI diets in persons with diabetes reported a reduction in HbA1c by 0.4 units (a 7.4 decrease) from Table 3. Epidemiologic studies on glycemic index (GI), glycemic load (GL), and fiber and effect on insulin resistance and risk of diabetes GI GL associated with risk of developing diabetes GI GL associated with risk GI GL associated with prevalence of insulin resistance No association GI GL and risk developing diabetes No association between GI and fasting insulin No association between GI GL with insulin-resistant diseases fiber beneficial association No association between GI...

The Unfolded Protein Response in Glucose Homeostasis and Diabetes

The metabolism of glucose is tightly controlled at the levels of synthesis and utilization through hormonal regulation. Glucose not only promotes the secretion of insulin but also stimulates insulin transcription and translation (Itoh and Okamoto 1980 Lang 1999 Permutt 1974). UPR signaling is essential to maintain glucose homeostasis. It is noteworthy that the UPR was first characterized as transcriptional activation of a set of genes, encoding glucose-regulated proteins, in response to glucose energy deprivation (Pouyssegur et al. 1977). We now know that pancreatic p cells uniquely require the UPR for survival during intermittent fluctuations in blood glucose (Harding et al. 2001 Scheuner 2001). Humans and mice with deletions in PERK have a profound pancreatic p cell dysfunction and develop infancy-onset diabetes (Delepine et al. 2000 Harding et al. 2001). Mice with a homozygous Ser51Ala mutation at the PERK phosphorylation site in eIF2a display a p cell loss in utero, suggesting...

Insulin administration and adjuvant therapies

Insulin is useful for controlling and avoiding hyperglycemia. If it is added to the parenteral nutrition bag, the suggested intake ranges from 1 IU per 10 g glucose in malnourished minimally stressed patients to 1 IU per 4 to 5 g of glucose in severely catabolic patients. When resistance is severe, it is safer to administer insulin (1-3 IU h) with a syringe pump. Several anabolic agents are effective in, or should improve the efficacy of, the conventional nutritional-metabolic approach to protein metabolism in stress conditions. Hormones like insulin, growth hormone, and insulin-like growth factors are particularly promising ( Wllmoie nd Carp ntjer 1994.).

Specific Metabolic Changes Associated With Type 1 Diabetes

Dietary factors, insulin adjustments and blood glucose values are so interdependent in women with Type 1 diabetes that one should not consider any one in isolation. Women with Type 1 diabetes have an absolute deficiency of insulin and their glycaemic control is totally dependent on exogenous insulin and dietary intake. The metabolic and physiological changes occurring in early pregnancy make these women especially vulnerable to hypoglycaemia, and this is further compounded if food intake falls due to pregnancy-induced nausea or vomiting. In later pregnancy, due to the increase in maternal lipolysis during the post-absorbative and fasting periods, ketoacidosis may develop rapidly. To minimise metabolic complications one needs to continually match and adjust the insulin doses to the carbohydrate intake. Maternal ketosis, as assessed by urine strips, is usually an indication for an increase in both dietary carbohydrate and insulin treatment. Diets need to be individual and flexible...

Specific Metabolic Changes Associated With Type 2 Diabetes

Women with Type 2 diabetes have a relative rather than an absolute deficiency of insulin. These women are already insulin-resistant and with the physiological increase in insulin resistance that occurs in pregnancy their insulin deficiency is further compromised. Very large doses of exogenous insulin are often required to obtain the necessary blood glucose target values. Avoiding excessive weight gain in these obese women being treated with large insulin doses requires considerable dietary education and intervention early in

Specific Metabolic Changes Associated With Gestational Diabetes

A degree of p-cell dysfunction is universal in women with GDM, both during and following pregnancy (50-52). Women who develop GDM not only have insufficient p-cell reserve to remain glucose-tolerant in pregnancy, but higher peripheral and hepatic insulin resistance than glucose-tolerant women (53). The p-cell defect is more apparent in the non-obese than obese GDM women in whom insulin resistance is often a greater contributing factor (54). These metabolic defects result in abnormalities of post-prandial lipoprotein metabolism (55) that can further reduce insulin sensitivity and compromise p-cell function (37,56). The diet should be aimed at lessening these metabolic abnormalities. As with the Type 2 diabetic women, most of the women who develop GDM are obese and weight gain targets should be set and a degree of energy restriction considered, see below. However, unlike the Type 2 diabetic women most can achieve adequate glycaemic control with diet alone. For this reason the dietary...

Diet And Insulin Therapy For

Once diet alone can no longer consistently ensure fasting glucose values below 5.5 mmol l and a 1 h post-prandial value below 7 mmol l, the introduction of insulin should be considered (63). It is important to recognise that a small proportion of women will require insulin early in pregnancy and not to assume dietary non-compliance (92). Those requiring insulin are the most metaboli-cally compromised and tend to have both the highest perinatal complications and the fastest deterioration to diabetes after pregnancy (93). Insulin is also occasionally introduced in later pregnancy for obstetric rather than glycaemic reasons this might occur for accelerated foetal growth or unexplained polyhydramnios (94). It is important to stress that once insulin is introduced for the management of GDM the dietary management remains equally important. The need to limit weight gain remains for obese women who now need to balance this with having sufficient carbohydrate snacks throughout the day to...

Obesity And Type 1 Diabetes

The strong association between obesity and Type 2 diabetes has generally overshadowed obesity in relation to Type 1 diabetes. Obesity is relevant, however, as increases in body fat stores generally dictate an increase in insulin requirements, mainly as a result of a further decline in insulin sensitivity. Conversely, excessive dosages of insulin can lead to weight gain, presumably through the lipogenic effects of hyperinsulinaeima and possibly compounded by overeating during the hypoglycaemic episodes, which become more frequent as insulin therapy is intensified. Weight gain, following intensive treatment of those with Type 1 diabetes, has been shown to induce unfavourable changes in lipid levels and blood pressure, similar to those observed in the insulin resistance syndrome (12). However, if intensive therapy results in improvements in glycaemic control, this can reduce the impact of weight gain on such cardiovascular risk factors (13). Of concern also is that obesity, or the fear...

The Association Between Obesity And Type 2 Diabetes

The link between obesity and Type 2 diabetes has long been established and a visit to any diabetes clinic will confirm the alarming statistic that 90 of those with Type 2 diabetes are also estimated to be obese (18). It is not currently known whether insulin resistance is the cause of obesity, the result of obesity, or whether the two conditions arise independently from each other (19). It is known that the prevalence of insulin resistance is greater among the obese, however, there are normal weight individuals who are equally insulin resistant (20). Without question, reduction in weight is associated with improvements in insulin sensitivity (21,22). It is also clear that regular physical activity improves insulin action, although the exact mechanisms involved are not clear. Several mechanisms have been proposed to explain how excessive body weight is associated with Type 2 diabetes. In general, the accumulation of fat mass is associated with a decline in whole body insulin...

Insulin Pump Treatment or Continuous Subcutaneous Insulin Infusion

Insulin pump therapy started in UK in 1976. Insulin pumps deliver a continuous basal insulin infusion (CSII) and patient-activated bolus doses at meal times. The pump is attached to the patients by an infusion set consisting of long flexible tubing with a needle or catheter on the end and is inserted subcuta-neously in the patient. In two meta-analysis CSII was compared with conventional insulin treatment 29,30 , which is not the actually used MDI. CSII caused a significant reduction in HbAlC of the size of 0.4-0.8 29,30 . This degree of improvement in glycaemic control for 10 years would reduce the number of patients developing retinopathy by about 5 29 . Using SIA for CSII provides a further small, but statistically significant improvement in glycaemic control (- 0.19 in HbAlC) as compared with regular insulin 31 . Therefore, the insulin of choice for CSII is now SIA. The frequency of hypo-glycaemia is less after CSII treatment rather than after MDI treatment in more recent studies...

The Insulinlike Growth Factor1 Ligand In Breast Cancer Management

Abstract The insulin-like growth factor-1 (IGF-1) system plays an important role in normal human development and is also a potent mitogen which can stimulate the development and progression of breast cancer cells. This review aims at looks at how measuring IGF-1 levels may be used in the clinical management of breast cancer patients. Many studies have shown that IGF-1 acts synergistically with oestrogen to stimulate breast cancer cells. Case-control studies have also shown that premenopausal women with high levels of serum IGF-1 have a high risk of developing breast cancer later in life which does not apply to postmenopausal women with correspondingly high serum levels. Serum IGF-1 levels can therefore potentially be used as biomarkers for predicting breast cancer risk while some studies have started using serum IGF-1 levels as a response bio-marker for chemopreventive drug trials. Measuring IGF-1 ligand expression in breast cancer tissue is not consistently associated with better or...

The Insulinlike Growth Factor1 Ligand

The IGF-1 gene is located on chromosome 12q22 and codes for A and B domains which are homologous to the A and B chains of the insulin hormone. The liver produces the largest amount of IGF-1 as a result of GH stimulation and is the main contributor to serum IGF-1. Serum IGF-1 can stimulate normal breast cells and promote malignant transformation as well as breast cancer progression via an endocrine fashion (18). Many studies have also shown that stromal cells adjacent to breast cancer cells can produce IGF-1 locally to stimulate tumour cells via an paracrine or autocrine mechanism (19-23). In fact, several studies have

Treatment with NPH Insulin and the Long Acting Insulin Analogues

One treatment concept has gained popularity in recent years following its success in clinical trials the addition of a long-acting basal insulin formulation to an existing oral antidiabetic drug (OAD) treatment, followed by aggressive titration of the insulin dose to achieve target levels of glycemia. Adding basal insulin has been shown to lower the entire 24-h blood glucose profile, and in combination with metformin the increase in weight after initiation of insulin treatment has been significantly reduced 9,10 . Both long-acting insulin analogues - insulin glargine and insulin detemir - have been implemented in the treat to target approach used in type 2 diabetic patients. The analogues are injectable, clear solutions, but the mechanisms by which they achieve prolonged activity differ entirely as described in detail in Chapter 8 and in 11,12 .

Growth hormone and insulin growth factor effects on metabolism

Growth hormone is secreted from the anterior pituitary gland in a pulsatile fashion following stimulation from hypothalamic growth hormone releasing hormone. Release of growth hormone is inhibited by somatostatin. Growth hormone binds to its own specific receptor and regulates the expression of insulin growth factor 1 (IGF-1) in many tissues, particularly the liver. The metabolic actions of IGF-1 are modulated by at least six different circulating binding proteins. Growth hormone causes lipolysis and antagonizes insulin effects, as well as having anabolic actions mediated by IGF-1. In fasting and serious illness there is a reduction in the indirect anabolic actions mediated by IGF-1 and an increase in lipolysis and insulin antagonism, probably associated with increased basal concentrations of growth hormone. Such changes might benefit fasting sick patients by providing circulating metabolic substrate.

Glucoseinsulin infusions

Insulin promotes potassium entry into cells by mechanisms separate from glucose entry glucose is also required to prevent hypoglycemia. There is no general agreement on the dose to be used. Commonly used prescriptions include 15 units of soluble insulin in 50 ml of 50 per cent glucose given centrally over 20 to 30 min, and 15 to 20 units of insulin in 500 ml of 10 or 20 per cent glucose over 30 to 60 min. All methods will reduce plasma potassium by approximately 1 mmol l over a period of 30 to 60 min and will usually maintain potassium at the lower level for 3 to 6 h, after which the treatment may be repeated. This may be sufficient to maintain plasma potassium levels at acceptable levels, but is usually inadequate in hypercatabolic patients and those with established renal failure in such cases it will buy time for definitive treatment.

Insulin Glargine Lantus

Insulin glargine (Lantus) was the first available long-acting human insulin analogue 12 . Glargine is a clear solution and there is no need to thoroughly mix it before injection. Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) differs from native insulin in that the 21 amino acid residue aspargine on the A chain has been substituted with a glycerine residue and 2 arginine residues have been added to the C terminus of the B chain, making glargine soluble in the acidic environment at pH of 4 12 . Glargine precipitates in the neutral pH of subcutaneous tissue, which prolongs its absorption to the blood. The addition of zinc as a hexamer-stabilising agent further prolongs the duration of action. Insulin glargine must not be mixed with other insulins 12 . Clamp studies in normal subjects and type 1 diabetic patients have confirmed that the duration of glargine is longer than NPH insulin and the action profile is flatter. Median duration of action is 23 h for glargine versus...

Diabetes Prevention Clinical Trials

The degree of body weight relative to height, commonly expressed as the body mass index, is a strong predictor of the development of type-2 diabetes 9 . This observation led to the obvious hypothesis that weight loss might lower a person's risk of developing type-2 diabetes. Three large randomized clinical trials have tested the hypothesis that dietary change in persons at high risk of type-2 diabetes can reduce the incidence of diabetes during a treatment period of several years. The first two employed diet and exercise interventions compared with each other 10 or combined 11 . The third, the US Diabetes Prevention Program, used a structured program of diet and exercise modification designed to produce weight loss compared with a program of diet and exercise advice only 4, 12 . It also included two pharmacologic treatment arms that will not be discussed here. Lifestyle modification lowered the incidence rate of diabetes in all three of these clinical trials 4, 10, 11 . The diet...

Insulin Detemir Levemir

In insulin detemir (B29lys(epsilon-tetradconoyl), des B30 human insulin) a 14-C fatty chain has been attached to position B29 and the amino residue at position B30 has been omitted 11,27 . When injected subcutaneous it dissociates exposing the fatty free acid chain, which subsequently binds to the free fatty acid binding sites on the albumin molecule 11,27 . Insulin detemir is 98-99 albumin bound in human plasma 11,27 . It is only the free fraction of detemir that is biologically active. The albumin binding and the ensuing slow release of detemir from albumin cause the prolonged blood glucose lowering effect of this insulin 27 . The soluble formulation ensures a homogenous concentration, with no need for resuspension before administration. The peak effect appears after 6-7 hours and the profile is more flat for detemir insulin compared with NPH insulin. The day-today variation in time action profile with detemir is much lower (CV 27 ) than with insulin glargine (CV 48 ) and NPH...

Comments on Insulin Detemir

The smooth time-action profile of detemir in combination with a low day-to-day variation of effect on glycaemic control seems to be translated into improved glycaemic control. If the average glucose levels are unchanged, then extreme high and low glucose excursions will be of lower frequency, and thus occurrence of hypo- and hyper-glycaemia will be reduced. At the simple level improved glycaemic control should be possible without increasing the risk of hypoglycaemia by the use of insulin detemir. In type 2 diabetes weight gain is problematic when starting insulin treatment and can act as a barrier to acceptance of insulin therapy. An interesting observation from the studies is the weight advantage of levemir compared with NPH insulin. Thus, during a 6-month period the weight gain was only 50 of that observed with NPH insulin.

Considerations In Managing Obesity Within Diabetes Care

It would be unusual to find the overweight patient with diabetes who has not at one time or another been advised to 'lose some weight'. For the patient faced with the prospect of attempting to achieve this it can be helpful first of all to quantify the amount of weight loss which we now know can bring clinically significant benefit, i.e. 5-10 of current body weight. Although the results of obesity surgery provide compelling evidence that an even greater amount of weight loss can significantly reduce the need for medication and in some cases eliminate the need for any further treatment, obesity surgery will not be appropriate for or accessible to many people with diabetes. It is important therefore that an achievable degree of weight loss is promoted and that a greater understanding of the benefits of a more modest amount of weight loss in the treatment of those with Type 2 diabetes is gained. In addition, with many studies demonstrating weight regain following a period of weight loss,...

Treatment of Patients with Type 2 Diabetes with Biphasic Premix Insulin

A popular alternative to treatment with a long-acting basal insulin plus OAD - the one pill, one shot regimen discussed above in patients with type 2 diabetes is a twice-daily biphasic premixed insulin combined with OAD. Along with a beneficial effect on prandial glucose control, biphasic premix insulin may reduce the risk of diabetic complication and cardiovascular disease 34 . Twice-daily biphasic premix insulin is often used as an initial insulin regimen and also as a substitute if basal insulin fails to achieve the HbAlc goal. Biphasic premix insulin is convenient to patients, but titration of the fix ratio of prandial and basal insulin may be difficult.

Comparison of Premix Insulin Analogues with Long Acting Insulin Analogues

In a 28-week study 209 subjects treated with OADs (except secretagogues) were randomised to BIasp 30 70 twice-daily or insulin glargine at bedtime and titrated to target blood glucose (4.0-5.5 mmol L) before breakfast and dinner for biphasic premix aspart (Blasp) and before breakfast for insulin glargine by algorithm-directed titration 23 . At the end of the study HbAlc was lower in Blasp 30 70 than in the glargine group (6.9 1.2 vs. 7.4 -1.2 ), especially for subjects with baseline HbAlc > 8.5 . More patients in the Blasp group reached target HbAlc below 7.0 than the glargine-treated patients (66 vs. 40 ) 23 . Reduction in HbAlc was 3.1 versus 2.4 , respectively (p < 0.05). The reduction in fasting plasma glucose was comparable between the groups. The number of minor hypoglycaemic episodes, weight gain (5.4 kg vs. 3.5 kg) and insulin dose (79 vs. 5l units per day) were greater in the Blasp group than in the glargine group 23 . In another 26-week study insulin naive type 2...

Insulin Resistance Syndrome

Reaven, at his Banting Lecture in 1988 (3), first proposed a widespread role for insulin resistance in common diseases such as coronary heart disease, Type 2 diabetes, obesity and hypertension. He proposed an insulin resistance syndrome (IRS) (or Syndrome X) as a unifying theory for a cluster of adverse metabolic changes (Table 9.1). Each of these changes have been independently shown to be related to a risk of cardiovascular disease. Insulin resistance is also a strong marker for the risk of developing Type 2 diabetes and therefore a Table 9.1 Metabolic and related disorders associated with the insulin resistance syndrome Table 9.1 Metabolic and related disorders associated with the insulin resistance syndrome

Comments on the Treatment with Biphasic Premix Insulin

The explanation for the results with biphasic pre-mix insulin versus basal insulins is that both postprandial and basal glycaemia are controlled by the biphasic premix insulin. In patients with high HbA1c, basal hyperglycemia plays a greater role for the HbA1c level than in a situation with low HbA1c, where postprandial hyper-glycemia contributes more to overall glycaemic control 44 . The biphasic premix insulin analogues have an advantage over basal insulin alone because they provide the rapid-acting insulin component that covers mealtime hyper-glycaemia. Therefore, it is not surprising that the premix insulin can reduce HbA1c more than intermediate-acting or the long-acting insulin analogues. Conversely, premixed regimens are relatively inflexible with their fixed ratio between the fast- and long-acting components. They can be difficult to intensify, because of risk of hypoglycaemia and weight gain.

Presence Of Insulin Resistance Before The Onset Of Type 2 Diabetes

It is interesting to note that although the incidence of people with diabetes in the UK is thought to be around 5 , the number of people with insulin resistance is nearer 25 (7). There are strong genetic determinants for the development of insulin resistance. The offspring of people with Type 2 diabetes have been shown to be more insulin resistant than those with no family history and this relationship is independent of obesity (8). Non-diabetic first-degree relatives of people with Type 2 diabetes also have similar thrombotic risk clustering to their diabetic relatives (9). In 1990 Haffner et al. (10) theorised that macrovascular complications start to develop very early on, initiated by insulin resistance and or hyperinsulinae-mia in the prediabetic state, whereas microvascular complications develop after sustained hyperglycaemia. In the Quebec heart disease study high fasting insulin concentrations were reported to be an independent predictor of ischaemic heart disease in men (11)....

Treating Subjects with Type 2 Diabetes with Multiple Injections Basal Bolus Therapy

Multiple injections with fast-acting insulin before the meals and intermediate or long-acting insulin at bedtime (basal-bolus regimen) is the first choice insulin regimen in most type 1 patients, but is not used very much in patients with type 2 diabetes. Nevertheless, prandial glucose regulation is an emerging concept, since epidemiological and mechanistic studies indicate that postprandial glucose contributes significantly to overall glycaemic exposure and also contributes to the vascular complications in type 2 diabetes 34,45 . Adding prandial insulin to basal insulin is a logical approach when the target of HbAlc cannot be achieved by the combination of basal insulin and oral therapy. Basal-bolus therapy represents the most physiological insulin regimen, but is more complex and the patient needs to be more educated and motivated for glucose monitoring. A few studies have evaluated the efficacy of multiple injections in type 2 diabetic patients. In the first study the efficacy and...

Obesity And Insulin Resistance

Obesity is the most common condition associated with insulin resistance (13). Obesity is a health problem reaching epidemic proportions in Western countries. In the UK alone some 16 of men and 18 of women are obese (14). Obesity can be defined as a body mass index (BMI) greater than 30kg m2. Insulin resistance is frequently observed in obese subjects and constitutes an independent risk factor for the development of Type 2 diabetes and atherosclerosis. The importance of increasing visceral fat (measured by waist hip ratio) as a risk factor for insulin resistance and cardiovascular disease has also been demonstrated (15). Weight loss improves insulin sensitivity and any type of therapy, whether it is dietary or pharmacological, that can aid effective weight loss and or weight maintenance will help prevent some of the deleterious metabolic changes associated with insulin resistance.

Summary Of Disturbances At A Cellular Level In Insulin Resistance

At a molecular level cellular factors have been identified that can markedly influence insulin action either directly or indirectly. These include tumour necrosis factor (TNF) a, glucose transporters (GLUT) and peroxisome proliferator activated receptor (PPAR)g, while increased glucose flux has been shown to induce insulin resistance in skeletal muscle. For a more detailed review see Garvey and Birnbaum (16). There is also likely to be a genetic predisposition to insulin resistance (17). Current treatments of Type 2 diabetes have little impact on reducing insulin resistance and this may explain why treating diabetes has only marginal benefits on reducing CHD mortality. It is hoped that with the introduction of thiazolidinediones, a novel class of oral agents that reduce insulin resistance, this may change. Environmental influences on insulin sensitivity are not yet completely understood. Exercise has a strong beneficial effect (18) and obesity a strong adverse effect. The effects of...

Treatment of Subjects with Type 2 Diabetes Using Pulmonary Inhalation of Insulin

Several pharmaceutical companies have developed inhaled insulin, and exubera from Sanofi aventis and Pfizer has been approved in several countries. The lungs with their large surface area and the thin alveolar epithelium allow rapid absorption of inhaled insulin 52 . The bioavailability has a range of 15-25 52 . The exubera insulin is a fine powder insulin in doses of 1 or 3 mg, corresponding to approximately 3 and 9 units of human insulin. The clinical trials have shown that the insulin antibody levels increase with the use of inhaled insulin, but this has not been linked to any changes in glycemic control and episodes of hypoglycaemia or allergic reactions 53 . The pharmacokinetic profile of exubera is quite similar to that of rapid-acting insulin analogues, but with a duration of action between that of rapid-acting analogues and fast-acting human insulin 54 . The development of inhaled insulin must be seen in the light of a substantial resistance to insulin therapy in patients with...

Comments on Inhaled Insulin

In type 2 patients the effect of inhaled insulin before meals on HbA1c did not seem to differ from that of fast-acting human insulin. Adding three times inhaled insulin to existing oral therapy is generally more effective than adding another oral hypoglycaemic agent. In the trials, subjects have been more satisfied with inhaled insulin than with subcutaneous insulin treatment. Whether this outcome will be borne out in clinical practice remains to be determined. Inhaled insulin seems to be most suitable in patients with controlled fasting blood glucose using a basal insulin. Smoking is a contraindication for inhaled insulin and inhaled insulin is not recommended in patients with asthma or chronic obstructive pulmonary disease. All candidates for inhaled insulin should have their lung function checked before and after 6 months and then every year. If lung function has declined more than 20 or by more than 500 ml from baseline, inhaled insulin should be discontinued. The long-term effect...

Fat And Insulin Sensitivity

Himsworth first made the association between increased dietary fat and insulin resistance in the 1930s and since then much has been published on these effects. In a recently published review on the subject by Storlien et al. (22), the premise was developed that the type of fatty acids eaten may be as important as the quantity of fat in the diet. High-fat diets, particularly high saturated fat, are associated with the development of Type 2 diabetes and glucose intolerance, while the intake of long-chain fatty acids, in particular n-3 fatty acids, seems protective. In addition the San Luis Valley Diabetes Study found that high saturated fat and low starch and fibre intakes were associated with hyperinsulinaemia in a non-diabetic population (23). It has also been demonstrated, using the euglycaemic hyperinsulinaemic clamp method, that increased monounsaturated fat improves insulin sensitivity and glycaemic control while having no adverse effects on lipids (24,25). The mechanism for this...

Carbohydrate And Insulin Sensitivity

Daly et al. (28) have recently reviewed the evidence and clinical implications of dietary carbohydrates and insulin sensitivity. This is a controversial area. Extensive studies in animals show a detrimental effect of diets very high in fructose or sucrose, particularly in association with induction of hypertrigly-ceridaemia. The more limited results in human studies show conflicting results, partly because of heterogeneity of design. Certain groups of subjects such as the elderly, sedentary subjects, those with established coronary artery disease, males and hyperinsulinaemic subjects may be more sensitive to very high intakes of sucrose and fructose than others.

Comparison of Biphasic Premix Insulin Analogues with Biphasic Premix Human Insulins

Several new biphasic premix insulin analogues have been introduced during the last years. Novomix 30, contains 30 rapid-acting aspart and 70 protamin - crystallised aspart. HumaLog (Mix 25), contains 25 rapid-acting lipro and 75 protamine-crystallised lispro. Biphasic premix analogues are available in other differently proportioned premix preparations, but these are used less frequently. The new premix insulin analogues can be injected immediately before a meal and the peak insulin concentration of the fast-acting component coincides with prandial glucose excursions 35 . The fast-acting component inhibits hepatic glucose production and promotes glucose uptake in the peripheral tissues and thereby reduces postprandial glucose excursions. The new biphasic premix insulin analogues have been compared with biphasic premix human insulin 36-40 . The degree of glycaemic control obtained has been similar to the human premix insulins and the premix analogues. In McNally's study the incidence of...

Current Dietary Recommendations As Applicable To The Older Person With Diabetes

The most recent European recommendations for adults with diabetes are shown in Table 10.1 (15). They emphasise energy balance and weight control, and recognise a wide variation in carbohydrate intake as being compatible with good diabetic control. The target of nutritional management is to help optimise glycaemic control and reduce the risk of cardiovascular disease and nephropathy. However, the quality of life of the individual person must be considered when defining nutritional objectives and health care providers must achieve a balance between the demands of metabolic control, risk factor management, patient well-being and safety. Compliance with all treatment modalities is likely to be compromised by increasing physical and mental disabilities, which occur more frequently in the ageing population. If beneficial changes to the diet of an elderly person with diabetes are to be achieved, access to dietetic services is needed. The following topics should be considered body weight,...

InsulinIGFI Signaling and Lifespan Regulation

One of the two main classes of the lifespan-extension mutations of C. elegans is related to the insulin IGF-I signaling. Insulin IGF-I signaling is mediated by the DAF-2 insulin IGF-I receptor. The daf-2 mutants that reduce the activity of DAF-2 remain youthful and active much longer than the wild-type animals and live more than twice as long reviewed in Ref. (9) . The lifespan-extension phenotype of the daf-2 is suppressed by mutations in daf-16, indicating that daf-16 is negatively regulated by DAF-2 signaling and is the major downstream effector. The daf-16 encodes a FOXO transcription factor (16,17). Binding of insulin IGF-I-like ligands to the DAF-2 insulin IGF-I receptor controls insulin IGF-I signaling. There are at least 38 genes (ins) encoding insulin IGF-I-like peptides in C. elegans (49,50). Many of these genes are divergent insulin superfamily members, and as the specific ligand has not yet been identified, these members may be possible to have complex and redundant roles....

InsulinIGFI Signaling Pathway and Stress Resistance

On the other hand, oxidative-stress resistance in two alleles of age-1 mutants (m333 and mg44) is not fully suppressed by daf-18 mutation, indicating that daf-18 does not act downstream of age-1. daf-16 and daf-18 act downstream of daf-2 in the insulin IGF-I signaling pathway for oxidative-stress resistance (23). Taken together, we postulate the following pathway for oxidative-stress resistance Thus, oxidative-stress resistance is closely associated with longevity but not with dauer formation. The PIP3 level is maintained under a balance between generation by AGE-1 PI3 kinase and degradation by DAF-18 PTEN, which could determine the impact of this pathway. The loss or reduction of function mutations in age-1 could reduce PI3 kinase activity to drop this second messenger level. When DAF-18 is reduced, only the preexisting pool of the second messenger may be insufficient to inhibit longevity and oxidative-stress resistance but sufficient to inhibit dauer formation. Dillin et al. (66)...

Insulinlike growth factors

The IGFs (also termed 'somatomedins'), constitute a family of two closely related (small) polypeptides IGF-I and IGF-II. As the names suggest, these growth factors bear a strong structural resemblance to insulin (or, more accurately, proinsulin). Infusion of IGF-I decreases circulating levels of insulin and glucagon, increases tissue glucose uptake and inhibits hepatic glucose export. IGFs display pluripotent activities, regulating the growth, activation, differentiation (and maintenance of the differentiated state) of a wide variety of cell and tissue types (Table 10.10). The full complexity and variety of their biological activities are only now beginning to be appreciated.

Metformin as First Line Pharmacotherapy of Type 2 Diabetes

A recently published consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) suggested using metformin as first-line pharmacotherapy not taking into account clinical characteristics such as obesity or body weight 22 . The authors recognized that for most individuals with type 2 diabetes, lifestyle interventions failed to achieve or maintain metabolic goals, either because of failure to lose weight, weight regain, progressive disease or a combination of factors. Therefore, they arrived at the consensus that (i) metformin therapy should be initiated concurrent with lifestyle intervention at diagnosis and (ii) metformin is recommended as the initial pharmacological therapy, in the absence of specific contraindications, for its effect on glycaemia, absence of weight gain and hypogly-caemia, generally low level of side effects, high level of acceptance and relatively low cost 22 . Metformin treatment should be titrated...

Thiazolidinediones Insulin Sensitizers

Thiazolidinediones are insulin-sensitizing agents used in the treatment of type 2 diabetes. Two of these agents are currently available for clinical use in the USA pioglitazone (Actos), and rosiglitazone (Avandia), both of which were approved by the Food and Drug Administration (FDA) in 1999. Troglitazone (Rezulin), the first clinically available thiazolidinedione, was withdrawn in March 2000 due to concerns about severe liver toxicity and has now been replaced by these newer agents, which have demonstrated hepatic safety.

Pathophysiology of Diabetes

Type-1 diabetes is associated with autoantibodies and activated lymphocytes which are reactive with p cell antigens 16 . Its course is characterized by a symptomless prediabetic phase whose presence can be inferred from immune markers. Pre-type-1 diabetes is a period of accelerated p cell loss, whose tempo varies from acute in those who present young to subacute or chronic in those who present later in life 17 . The differences in tempo are assumed to be under genetic control, since those who develop type-1 diabetes in childhood tend to carry more intensely responsive HLA genes than those who develop it later in life 18, 19 . p cell autoimmunity appears to start early in life, insofar as immune markers predictive of future diabetes can be present as early as at 9 months of age 20 . Type-2 diabetes is characterised by a combination of insulin resistance and defective insulin response that results from it 21 . Blood insulin concentrations are raised, at least initially, but are never...

Effects on Pancreatic Insulin Secretion

Clinical use of thiazolidinediones consistently results in reduced plasma insulin levels and reduced insulin requirements in patients with type 2 diabetes taking insulin, reflecting an increase in insulin sensitivity. Although these agents do not directly stimulate P-cell insulin secretion, studies indicate that they can restore aspects of defective glucose-coupled insulin responsiveness in humans and animals with type 2 diabetes. There are several potential mechanisms whereby thiazolidinediones might enhance P-cell function, in addition to simply lowering ambient levels of glycemia and reducing glucotoxic signaling abnormalities in P-cells. Recently, abnormal P-cell secretory responsiveness and potential cell death (apoptosis) have been attributed to chronic effects of accumulated triglycerides and FFA derivatives in the pancreatic islet cells in obesity with insulin resistance, a phenomenon that has been dubbed lipotoxicity 12,13 . This hypothesis also postulates that the effect of...

Inhibition of insulinstimulated glucose uptake by hyperosmotic stress

Like several other insulinomimetic agents, hyperosmolarity not only partially activates several insulin-specific biological responses, but also induces a state of insulin resistance. To evaluate this, the following protocol is used. 3. One hundred microliters of insulin (5 nM in KRP buffer supplemented with 0.2 BSA) is added per well of six-well plates for 15 min.

The Epidemiology of Diabetes

Over the past 20 years, the incidence of type-2 diabetes in the western world has increased dramatically, a pattern that parallels closely the rising incidence of obesity and (by implication) that of insulin resistance 37 . Furthermore, age at presentation has been falling, such that the incidence of type-2 diabetes in American adolescents has increased 10-fold and in Japanese school children 36-fold within a generation 38 . Rather strikingly, Fig. 2. Evidence for the progressive rise in insulin resistance (body mass) deemed by the accelerator hypothesis to be the environmental trigger for type-1 diabetes from 36 . Fig. 2. Evidence for the progressive rise in insulin resistance (body mass) deemed by the accelerator hypothesis to be the environmental trigger for type-1 diabetes from 36 . the same pattern of increasing incidence and younger age at presentation has occurred for type-1 diabetes over the same time period. Several studies in Europe show a doubling in incidence of type-1...

Prevention of Diabetes

A recent study 26 examined the effects of rosigli-tazone in the prevention of type 2 diabetes. The double-blind, randomized controlled trial consisted of 5,269 patients with either impaired fasting glucose or impaired glucose intolerance. They were assigned to receive rosiglitazone 8 mg daily versus placebo for approximately 3 years. The outcomes revealed a significant difference in the development of diabetes in the rosiglitazone-treated group (11 ) versus placebo (26 ). The rosiglitazone group also showed a significant regression to nor-moglycemia (50 ) versus placebo (30 ). There was, however, a small but statistically significant number of heart failure cases, which occurred in the rosiglitazone group (0.5 ) versus placebo (0.1 ). The trial concluded that an 8-mg dose of rosiglitazone daily, can prevent the development of diabetes in > 60 of patients with impaired fasting glucose or impaired glucose tolerance.

The Scientific Basis For Recommending Highmufa Diets For Diabetes

Many diabetes experts argue in favour of allowing a higher MUFA intake for people with diabetes, on the grounds that high-carbohydrate diets can increase blood glucose, insulin and TG levels and reduce HDL-cholesterol levels. A meta-analysis of nine studies with a total of 133 subjects comparing these two approaches to diet therapy in patients with diabetes revealed that high-MUFA diets (22-33 of energy intake total fat 37-50 energy) improved lipoprotein profiles as well as glycaemic control (19). Compared to high-carbohydrate diets (50-60 energy intake), high-MUFA diets reduced fasting TG and VLDL-cholesterol levels by about 20 and caused a modest increase in HDL-cholesterol (4 ) but had no effect on LDL-cholesterol. There was no evidence that high-MUFA diets induced weight gain in these tightly controlled studies. However, there are several limitations that need to be raised before deciding whether they provide sufficient evidence to formulate recommendations for therapeutic diets...

Body Mass The Elusive Trigger of Type1 Diabetes

If the rising incidence and earlier presentation of diabetes were to be explained by an ever heavier population at all ages, weight gain would have as much a role in the changes of demography of type-1 diabetes as it does in that of type 2. Ascribing the rising incidence of type-1 diabetes to metabolic, rather than to immunological, factors has novel and important implications. Clinical research over the past 30 years has focused almost exclusively on exogenous factors (viruses, toxins, allergens) deemed able to initiate, facilitate or intensify autoimmune damage to the p cell. Although many have been proposed 49 , none has been confirmed. The prevalence of obesity meanwhile has trebled. Insulin resistance, resulting from a combination of obesity and physical inactivity, is a serious candidate for the 'elusive' environmental factor responsible for the rising incidence of type-1 diabetes and, as such, a true accelerator.

Which Diet Is Best For Improving Insulin Sensitivity

The body's sensitivity to the hormone insulin predicts how well it handles a meal containing carbohydrate, i.e. how easily and quickly it restores normal glucose levels after consumption. In insulin-resistant states, large amounts of insulin are needed to restore euglycaemia and glucose and or insulin levels may still be high 2h later. In Type 2 diabetes, insulin resistance is often severe and is combined with impairments in insulin secretory capacity. Obesity, particularly abdominal obesity, is known to worsen insulin resistance and increase the risk of Type 2 diabetes (46). The degree of insulin sensitivity is also affected by the energy content and macronutrient composition of the diet. Epidemiological and dietary intervention studies in humans indicate that a high-fat, energy-dense diet promotes weight gain and the development of obesity (47), impairs insulin sensitivity and increases the risk of developing Type 2 diabetes (48). Relatively high intakes of saturated fat appear to...

Ts in Organ Specific Microvascular Alterations in Diabetes

Diabetic retinopathy (DR) predominantly affects the vascular components of the retina. Early in the disease course, diabetes causes functional alterations such as reduced retinal blood flow 2 . With sustained hyperglycemia structural changes such as capillary BM thickening, loss of pericytes, and breakdown of intracellular endothelial cell junctions occur. With respect to structural changes, we have demonstrated that ET receptor blockade with dual ETA and ETB antagonist, bosentan, prevents diabetes-induced upregulation of FN and collagen alpha-1 (IV) mRNA, and increased capillary BM thickening in animals 1 . ETs could also arbitrate later stages of DR as selective ETB receptor antagonists can prevent endothelial cell proliferation and migration, two fundamental steps in the process of angiogenesis. In a few recent studies, vitreous ET-1 levels were found to be significantly elevated in patients with proliferative DR as compared to nondiabetic subjects 10 . Diabetic Nephropathy...

Evidence For Sucrose Restriction In Diabetic Diets

Many randomised, controlled trials have shown that the isocaloric substitution of moderate amounts of refined sucrose for starch in diabetic diets has no adverse effects on blood glucose or lipid levels in people with diabetes (69-71). In fact, several studies show improved glycaemic control, especially in children with Type 1 diabetes (72). This makes sense when we consider that most foods containing sugar have a GI less than 60, while that of most modern starchy foods is over 70 (37,73). Many diabetes associations now officially recognise that sucrose restriction is not necessary in diabetic diets, although some put an upper limit of 30 g per day (the average intake in the non-diabetic population is about 60 g per day). Unfortunately, the dietary dogma of sucrose avoidance in diabetic diets is so well entrenched in the mind of the public and most health professionals that little change has occurred in practice. Intense sweeteners and low-joule soft drinks are almost universally...

Posttransplant Diabetes Mellitus

Anywhere from 5-40 of recipients of renal allografts will develop posttransplant diabetes mellitus (PTDM). This hyperglycemia is generally medication-related. Corticosteroids increase gluconeogenesis, and produce end organ resistance to insulin effect. Both CsA and Tacrolimus directly inhibit islet cell release of insulin and are additive in their effect on blood glucose with corti-costeroids. It appears that increase in age, a positive family history for diabetes, and African American race all predispose to the development of PTDM. Clinically, Tacrolimus appears to produce more hyperglycemia than CsA. Treatment of PTDM may respond to dietary counseling as well as judicial lowering of steroids or calcineurin inhibitors. Oral hypoglycemics are frequently used and one must remember that most of these have at least partial renal excretion and therefore must be used carefully in patients with renal impairment. Troglitazone (Rezulin) seems to induce the cytochrome IIIA system and can...

Plasma Glucose And Insulin Concentrations

Several studies have been published describing the effect of reciprocal increases in CHO and decreases in fat intake on plasma glucose and insulin concentration in patients with Type 2 diabetes (15,17-20). Furthermore, the results have been remarkably similar, given the differences in the experimental protocols, and quite consistent with what would have been predicted in view of the pathophysiology of this syndrome. If CHO intake is increased in patients with Type 2 diabetes, plasma glucose concentrations will tend to rise, stimulating the pancreas to secrete more insulin. If patients with Type 2 diabetes retain significant B-cell reserve, more insulin will be secreted in this situation, attenuating any rise in plasma glucose concentrations at the expense of higher plasma insulin concentrations. Conversely, the less able the patient is to secrete additional amounts of insulin in response to an increase in CHO intake, the greater will be the rise in plasma glucose concentration, with...

Obesity and Type 2 Diabetes

During the last 20 years, obesity has reached epidemic proportions in the United States and worldwide. Recent data from the National Center for Health Statistics indicate that 30 of U.S. adults 20 years of age and older (over 60 million people) are obese (Ogden, Carroll, Curtin, McDowell, Tabak, and Flegal 2006). Visceral obesity and three other pathologic conditions (dyslipidemia, hypertension, and insulin resistance) comprise the so-called metabolic syndrome, also known as Syndrome X. Syndrome X is a major risk factor for type 2 diabetes (T2D also called non-insulin-dependent diabetes mellitus, or NIDDM) (Haffner, Ruilope, Dahlof, Abadie, Kupfer, and Zannad 2006). A common feature of obesity, insulin resistance, and T2D is chronic, low-grade inflammation (Dandona, Aljada, and Bandyopadhyay 2004 Dandona, Aljada, Chaudhuri, Mohanty, and Garg 2005 Weisberg et al. 2006 Weisberg, McCann, Desai, Rosenbaum, Leibel, and Ferrante 2003 Wellen and Hotamisligil 2005). Markers of chronic...

Obesity and Type2 Diabetes

Epidemiological studies show that increasing body weight is associated with an increasing risk for type-2 diabetes (T2D) 1 . More than 90 of individuals with T2D are obese. Conversely the prevalence of T2D is 46 among individuals with a BMI of 30 (kg m2) and higher. Obesity is a contributing factor in the development of T2D in an estimated 60-90 of patients with this condition 2 . The data indicate that the current epidemic obesity may be the major causative factor in the worldwide increase of the prevalence of diabetes.

Medical Nutrition Therapy in Diabetes

But current nutritional recommendations for patients with T2D in general do not attach great importance to weight loss. The goals of medical nutrition therapy aimed at by the ADA focus on attaining and maintaining optimal metabolic outcomes, on preventing and treating the chronic complications of diabetes, on improving health through healthy food choices and physical activity, and on addressing individual nutritional needs 12 . There is evidence that all these goals are easily reached or somewhat better reached with a reduction of body weight. However, it seems to be a common belief among physicians that nutritional therapy in T2D is not efficient. To optimize glycemic control physicians often start with drug or insulin therapy before the effects of diet treatment are assessable 13 . In view of recent consistent and strong evidence that weight reduction improves insulin sensitivity and glycemic control in T2D, the Joslin Diabetes Center and Joslin Clinic recommended clinical...

Management of Weight Loss in Diabetics

It has been reported that achievement of weight loss and weight maintenance in patients with T2D seems to be more difficult than in people without diabetes. Poor adherence to the dietary recommendations and physiological adaptations that occur with dieting 15 may explain the poor outcomes. In addition, intense blood glucose control in diabetics may counteract with weight loss efforts. The results of the UK Prospective Diabetes Study show a significant increase in weight in the intensive-treated group compared with the conventional diet group by 3.1 kg for the cohort at 10 years 16 . Thus, for weight loss in diabetic patients, programs are needed to increase the amount of weight loss and to facilitate and improve long-term weight maintenance.

Lack of First Phase Insulin Response in T2D Subjects

Besides the reduced insulin-mediated glucose uptake in skeletal muscle (and in liver and fat tissue), the abnormal insulin secretion pattern characterised by a lack of first-phase insulin release may also play a pathophysiological role, since the postprandial insulin peaks disappear in T2D subjects (Fig. 3). A recent publication has shown that the reduction of the first-phase insulin response to meals is already present at normal fasting glucose values in T2D subjects 13 . This indicates a need for an earlier insulin treatment than what has been the routine for several years. Furthermore, these findings indicate that it is unphysiological to treat Endogenous sulin Insulin Aspart Fig. 3. Twenty-four-hour blood glucose (a) and insulin (b) values together with insulin aspart values (c) after 6 months of treatment with either NPH insulin (control group) or triple therapy. (d) The scattered area represents the 24-h insulin profile in healthy non-diabetic subjects in hospital. Eight-point...

Different types of diabetes

The disease diabetes mellitus, if untreated, is characterised by intense thirst and frequent urination. Hence its name diabetes, from the Greek for syphon. The term mellitus means to do with honey - i.e. sweet. It refers to the fact that the urine is sticky and sweet with glucose. There is a completely different, and much rarer, disease also called diabetes this is diabetes insipidus. Diabetes insipidus is also characterised by thirst and urination, but the urine is insipid or watery, and not sweet. Diabetes insipidus is caused by a failure of the antidiuretic hormone (also called vasopressin - see Section 5.3.2) to act, either because of a lack of the hormone, or because of a defect in the receptors for antidiuretic hormone in the kidney. Diabetes insipidus will not be considered further here. Diabetes mellitus (which will be referred to simply as diabetes in this chapter) can itself be divided into two main types (Table 10.1). In one, the disease usually develops during childhood or...

On Prevention and Management of Type2 Diabetes

Physical activity has impacts on metabolism that seem to improve management of type-2 diabetes independent of weight loss 1, 7, 8 . Increased physical activity reduces insulin resistance, improves insulin sensitivity, and increases glucose disposal rates even independent of changes in body weight or body fatness 1, 7, 8 . In addition to insulin resistance and glycemic control, other factors which likely play a role in causing exercise impairments and which might be amenable to treatment include endothelial dysfunction, cardiac abnormalities and mitochondrial abnormalities 7, 8 .

Type 2 diabetes mellitus

Type 2 diabetes mellitus does not result so clearly from insulin deficiency. Defects in insulin secretion in people with Type 2 diabetes can be unmasked by laboratory tests in particular, the initial phase of insulin secretion in response to a glucose load appears to be defective at an early stage in the disease. However, the prominent defect in Type 2 diabetes is not so much a deficiency of insulin, as a failure of insulin, at relatively normal concentrations, to exert its normal effects this is the condition known as insulin resistance (Fig. 10.2). Insulin resistance may have widespread effects (Box 10.1). Insulin resistance is also a prominent feature of obesity (see Section 11.4.4). One very plausible hypothesis for the development of Type 2 diabetes is the following. When people become obese, their tissues become resistant to the ac-

Alterations in metabolism in diabetes mellitus

It is important to draw a distinction here between the metabolic alterations that occur in untreated diabetes mellitus, and those which occur in people with the disease nowadays, who usually receive treatment. The former may be studied in animal models of the disease in which drugs which are selectively toxic to the pancreatic islets are given to abolish or severely restrict insulin secretion. It is a mistake to think, however, that people with treated diabetes are free from metabolic problems. It is now rare, at least in the developed world, for them to die from acute lack of insulin. But their life expectancy is reduced, and their quality of life may be reduced by progressive onset of so-called diabetic complications. These will be considered further below, together with the reasons why treatment does not always produce a totally healthy individual.

Activity of the Entero Insular Axis and Incretin Hormones in Type 2Diabetic Patients

Reduced Incretin Effect in Patients with Type 2 Diabetes In healthy human subjects oral glucose elicits a considerably higher insulin secretory response than does intravenous glucose (even if leading to the same glycemic increments). This incretin effect is substantially reduced or even completely lost in patients with type 2 diabetes 86 . The reduction in the incretin effect probably is an acquired defect, since it is also found in patients with diabetes secondary to chronic pancreatitis, whereas chronic pancreatitis without diabetes is characterized by a normal incretin effect 87 . Secretion of Incretin Hormones in Patients with Type 2 Diabetes Cross-sectional analyses of larger cohorts suggest that there is a slight reduction in postprandial GLP-1 secretion following the ingestion of a mixed meal in patients with type 2 diabetes. Subjects with impaired glucose tolerance display intermediate results between healthy controls (normal response) and type 2-diabetic patients (reduced...

Antidiabetic Actions of GLP1

Short-term intravenous infusions of GLP-1 (approximately 1.2 pmol kg min, leading to pharmacological plasma concentrations of total GLP-1 of approximately 100 pmol L, and intact biologically active GLP-1 of approximately 15 pmol L) lower blood glucose in human subjects with type 2 diabetes through a transient glucose-dependent stimulation of insulin and suppression of glucagon secretion and gastric emptying 110-113 . A 6-week subcutaneous infusion of GLP-1 in patients with type 2 diabetes achieving plasma levels of total GLP-1 of around 65 pmol L 114 was followed by a substantial improvement in insulin secretory capacity, insulin sensitivity, a reduction in HbA1c by 1.2 , and weight loss 114 . Although intravenous or subcutaneous GLP-1 infusions may be useful for the short-term control of hyperglycemia under a variety of clinical conditions 115,116 , the long-term treatment of type 2 diabetes requires a more feasible approach for achieving sustained GLP-1 receptor activation. The...

Biochemical and Pharmacological Actions of Insulin

The biochemical actions of insulin are complex and involve many steps to integrate carbohydrate, protein, and lipid metabolism for the maintenance of fuel homeostasis. In addition to its effects on stimulating glucose uptake by tissues, insulin has five major physiological effects on fuel homeostasis. It can (1) diminish hepatic glycogenolysis by inhibiting glycogen phospho-rylase (2) promote hepatic glucose storage into glycogen by stimulating glycogen synthetase (3) inhibit hepatic gluconeogenesis (i.e., convert noncarbohydrate substrates like amino acids into glucose) (4) inhibit lipolysis by inhibiting hormone-sensitive lipase activity, thereby decreasing plasma free fatty acid and glycerol levels and (5) promote the active transport of amino acids into cells for incorporation into protein, thereby producing a net positive nitrogen balance. The biological actions of insulin are initiated following a reversible binding of the hormone to a high-affinity specific insulin receptor on...

Clinical Management Of Diabetes

Diet is the cornerstone of the management of diabetes, regardless of the severity of the symptoms or the type of diabetes. Exercise is also an important component in managing diabetes, particularly in obese individuals with NIDDM who may have a component of insulin resistance as a consequence of obesity. Treatment regimens that have proved effective include a calorie-restricted diet in combination with exogenous insulin or oral hypoglycemic drugs. However, since diet, exercise, and oral hypoglycemic drugs (Table 67.2), often because of noncompliance by the patient, will not always achieve the clinical objectives of controlling the symptoms of diabetes, insulin remains universally important in therapeutic management. The administration of insulin is required for the treatment of type I (IDDM) and in cases of type II (NIDDM) that are refractory to management with oral hypoglycemic drugs. Because the spectrum of patients with diabetes extends from the totally asymptomatic individual to...

Oral Agents For Treating Diabetes Mellitus

Although insulin has the disadvantage of having to be injected, it is without question the most uniformly effective treatment of diabetes mellitus. Some milder forms of diabetes mellitus that do not respond to diet management or weight loss and exercise can be treated with oral hypoglycemic agents. The success of oral hy-poglycemic drug therapy is usually based on a restoration of normal blood glucose levels and the absence of glycosuria. Traditionally, the term oral hypoglycemic was used interchangeably with sulfonylureas, but more recently the development of several new drugs has broadened this designation to include all oral medications for diabetes. Because these drugs do not have to be injected, oral agents enhance compliance in type II diabetics. These classes of drugs are not generally used in type I diabetes. The pharmacokinetic profile of oral agents for diabetes is depicted in Table 67.4.

Renal Transplantation And Diabetes

End stage renal failure (ESRF) from diabetes is increasing and the number of diabetic patients receiving a renal transplant is growing. Diabetes is also a common metabolic complication following a successful renal transplant, due partly to the steroids used to prevent graft rejection and to the associated weight gain they cause. In one study involving 114 patients with normal glucose tolerance, a week before transplantation, only 36 (32 ) retained normal glucose tolerance 9 to 12 months post-transplant with 27 (24 ) patients becoming frankly diabetic. Both p-cell dysfunction and insulin resistance contribute to the development of diabetes post-transplant (1,2).

Prevention of Type2 Diabetes

During the last few years well-conducted, randomized studies have unequivocally shown that type-2 diabetes mellitus can be effectively prevented or delayed by lifestyle modification programs in people at risk of developing it 2-4 . The ADA, the DNSG of the EASD and Diabetes UK have incorporated diabetes prevention guidelines in their nutritional recommendations. The ADA gives emphasis to the fact that structured programs that focus on lifestyle changes, including education, reduced fat and energy intake, regular physical activity and regular participant contact, can reduce the risk of developing diabetes. The DNSG of the EASD state that weight reduction and maintenance of weight loss in overweight individuals is a critical component of the lifestyle modification program, which may be expected to reduce the risk of developing type-2 diabetes. The appropriate macronutrient composition of the diet is a total fat < 30 of energy intake, saturated fat < 10 and fiber intake > 15g...

The Molecular Endocrinology Of Diabetes Mellitus

Diabetes mellitus is a metabolic syndrome characterized by hyperglycemia resulting from variable defects in insulin secretion and action. Traditionally, diabetes mellitus has been divided into four categories Type 1 diabetes, characterized by absolute insulin deficiency and requirement of insulin therapy to sustain life Type 2 diabetes, characterized by variable defects in insulin secretion and action, without an absolute need for insulin therapy (although insulin might be necessary for adequate control of hyperglycemia) other specific types of diabetes and gesta-tional diabetes. Type 1 diabetes is further subdivided into Type 1A, or autoimmune, diabetes and Type 1B, or idiopathic diabetes. The other category is very large, encompassing diabetes resulting from other illness or medications (such as cystic fibrosis-related diabetes) as well as many genetic syndromes that include diabetes (101). It is becoming increasingly apparent, however, that these categories are artificial and that...

Insulin Like Growth Factors Insulin IGFs 1 and

- Insulin is produced as proinsulin Steiner and Oyer 1967 by the P cells of the islets of Langerhans in the pancreas. The mature Insulin Receptor is derived from precursor polypeptides. It consists of two a subunits (1,370 amino acids or 1,382 amino acids, generated by alternative splicing) and two P subunits (624 amino acids). The a subunits are extracellular, while the P subunits traverse the membrane and possess tyrosine kinase activity. The proto-oncogene ros encodes the Insulin Receptor P chain. Although several receptors for IGFs exist, the biological actions of IGF-1 and IGF-2 are predominantly exerted through the type-1 IGF-1R, which binds IGF-1 and IGF-2 with high affinity. Activation of the IGF-1R occurs following IGF-1 binding to the a subunit of the IGF-1R on epithelial cells, leading to autophosphorylation of the P subunit. The IGF-1R displays potent mitogenic, antiapoptotic, and transforming activities, which may be a prerequisite for oncogenesis. IGF-1R is a...

Formulation of insulin products

Intermediate Acting Insulin Peak

Insulin, whatever its source, may be formulated in a number of ways, generally in order to alter its pharmacokinetic profile. Fast (short)-acting insulins are those preparations that yield an elevated blood insulin concentration relatively quickly after their administration (which is usually by s.c. or, less commonly, by i.m. injection). Slow-acting insulins, on the other hand, enter the circulation Table 11.3 Native and engineered human insulin preparations that have gained approval for general medical use. Reproduced in updated form with permission from Walsh, G. 2005. Therapeutic insulins and their large-scale manufacture. Applied Microbiology and Biotechnology, 67, 151-159 Recombinant products of native human insulin sequence Humulin Engineered insulins Humalog (Insulin lispro) Liprolog (Insulin lispro) NovoRapid (Insulin Aspart) Novolog (Insulin Aspart) Levemir (Insulin detemir) Apidra (Insulin Glulisine) Lantus (Insulin glargine optisulin) Recombinant human insulin produced in...

Insulin and triacylglycerol metabolism

The enzyme lipoprotein lipase is activated in adipose tissue by insulin, as noted in previous chapters (see Section 4.5.3.1). Thus, in the postprandial period, clearance of the triacylglycerol-rich lipoproteins is increased, and this increase in clearance occurs at the time of the peak triacylglycerol concentration in plasma, a few hours after a fatty meal. The removal of chylomicron-triacyl-glycerol is a saturable process, reflecting limited activity of lipoprotein lipase. After a fat-rich meal this pathway may become saturated. Both chylomicrons and VLDL compete for hydrolysis by lipoprotein lipase, a process that has been termed the common saturable removal mechanism. For reasons that are not entirely clear, lipoprotein lipase acts preferentially on larger particles, so chylomicrons tend to 'win'. One corollary of this competition is that the rapidity of clearance of excess triacylglycerol from the plasma in the postprandial period (i.e. after a meal) is dependent upon the...

Conventional Intensified Insulin Therapy or Multiple Daily Insulin Injections MDI

In conventional intensified insulin therapy (MDI) using the basal-bolus approach with MDI, continuous basal insulin supply is obtained by once- or twice-daily subcutaneous injections of longer-acting preparations, supplemented by mealtime injections of more rapid-acting formulations. Rapid-Acting (Mealtime) Insulins These include structurally unchanged regular insulin preparations and short-acting insulin analogues (SIAs), which dissociate more rapidly than regular insulins and are absorbed faster. The glucose-lowering effect of rapid-acting insulins is enhanced by exercise within 1-3 h after the meal and by reducing the carbohydrate content of the meals. Regular (Soluble) Insulins Following subcutaneous injection of structurally unchanged regular insulin preparations, the native insulin tends to associate a hexameric form, which is slowly dissociated to single molecules and absorbed, thereby interfering with recreation of the physiological prandial insulin response (Table 1). Table...

Production of human insulin by recombinant DNA technology

Human insulin produced by recombinant DNA technology was first approved for general medical use in 1982, initially in the USA, West Germany, the UK and The Netherlands. As such, it was the first product of recombinant DNA technology to be approved for therapeutic use in humans. From the 1990s on, several engineered insulin products (discussed later) also gained approval (Table 11.3). The initial approach to recombinant insulin production taken entailed inserting the nucleotide sequence coding for the insulin A- and B-chains into two different E. coli cells (both strain K12). These cells were then cultured separately in large-scale fermentation vessels, with subsequent chromatographic purification of the insulin chains produced. The A- and B-chains are then incubated together under appropriate oxidizing conditions in order to promote interchain disulfide bond formation, forming 'human insulin crb' An alternative method (developed in the Eli Lilly research laboratories), entails...

Lactic Acid and Insulin

Insulin may stimulate cell proliferation and angiogene-sis. Among its effects, insulin stimulates hypoxic cells to produce greater amounts of lactic acid. One way to regulate insulin production is through dietary modifications. When food is digested, its carbohydrate content is converted to glucose, and elevated plasma concentrations of glucose stimulate the secretion of insulin. Foods that are slowly converted to glucose raise insulin levels less dramatically than foods that contain glucose or are easily converted to glucose. The ability of foods to increase insulin concentrations is referred to as their glycemic index. Thus, insulin secretion can be kept to a minimum by eating foods that have a low glycemic index, such as vegetables and protein and, to a lesser extent, whole grains and beans. The glycemic index has been used extensively by diabetic patients to control their insulin requirements. Some natural compounds have also been reported to inhibit the cancer-promoting effects...

Mechanism of ET Alteration in Diabetes

Alteration of ETs has been demonstrated in both type I and type II diabetes. Although a number of studies can be cited that provide contradictory reports of plasma ET levels in diabetic patients, it should be noted that these peptides act in both an autocrine and paracrine fashion. Therefore, plasma levels may not provide an adequate assessment of their biological activity 1 . In both animal and human diabetes, use of ET antagonists may be more revealing in terms of the consequences of ET alteration. We and others have demonstrated that in endothelial cells and in several target organs of diabetic complications, ETs are upregulated and mediate structural and functional alterations 1 . The mechanisms by which sustained hyperglycemia leads to upregulation of ETs include activation of PKC, augmented polyol pathway and pseudohypoxia, oxidative stress, elaboration of growth factors, and alteration of vasoactive factors such as NO. Mechanisms and consequences of ET alteration in diabetes...

Insulin Resistance Hyperinsulinemia and the IRS

Insulin resistance is not a disease, but a physiological abnormality that increases the likelihood that one or more of the abnormalities listed in Table 2 will be present. Furthermore, because the abnormalities seen in Table 2 occur more commonly in insulin-resistant individuals, they are at increased risk to develop one or more of the clinical syndromes listed in Table 3. However, the relationship between insulin resistance and the changes seen in Tables 2 and 3 is complicated, and the abnormalities and clinical syndromes listed in these tables can occur in the absence of insulin resistance. It must also be emphasized that insulin-resistant individuals do not necessarily develop any of the clinical syndromes listed in Table 3. The focus of this chapter does not permit an extensive discussion of the complex relationship between insulin resistance, compensatory hyperin-sulinemia, and the abnormalities and clinical syndromes that makeup the IRS, and reviews of these issues are available...

The insulin receptor and signal transduction

The insulin receptor is a tetrameric integral membrane glycoprotein consisting of two 735 amino acid a-chains and two 620 amino acid P-chains. These are held together by disulfide linkages (Figure 11.2). The a-chain resides entirely on the extracellular side of the plasma membrane and contains the cysteine-rich insulin-binding domain. Each P-subunit is composed of three regions the extracellular domain, the transmembrane domain and a large cytoplasmic domain that displays tyrosine kinase activity. In the absence of bovine insulin, tyrosine kinase activity is very weak. Proteolytic digestion of the a-subunit results in activation of this kinase activity. It is believed that the intact a-subunit exerts a negative influence on the endogenous kinase of the P-subunit and that binding of insulin, by causing a confor-mational shift in a-subunits, relieves this negative influence. The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the 'juxtam-embrane domain',...

Treating And Preventing Diabetes

Proteins play many important roles in living organisms. The hormone insulin is a protein that stimulates cells to take up glucose. More than 18 million Americans have diabetes, an inability of the body to make or respond to insulin. When the body cannot make or respond to insulin, the body's cells must switch to burning mainly fat as their fuel. The resulting high levels of fat in the blood can cause cardiovascular disease. In addition, the glucose that accumulates in the blood causes other problems. For example, diabetes can have serious complications, including kidney disease, heart failure, blindness, and amputation of the lower limbs. Some symptoms of diabetes include increased thirst, frequent urination, fatigue, and weight loss. Regular physical activity can help reduce the risk of developing type 2 diabetes. Regular physical activity can help reduce the risk of developing type 2 diabetes. Type 1 Diabetes Between 5 and 10 percent of people who suffer from diabetes have type 1...

Adverse Reactions to Insulin Therapy

The most common side effect associated with insulin therapy is hypoglycemia, which may result in such CNS symptoms as tremors, lethargy, hunger, confusion, motor and sensory deficits, seizures, and unconsciousness. Adrenergic manifestations include anxiety, palpitations, tachycardia, and diaphoresis. In many cases, diabetics are aware that hypoglycemia is developing, and prompt administration of oral carbohydrates (e.g., fruit juice or glucose tablets) can restore normoglycemia. In more severe cases (e.g., unconsciousness, seizures), intravenous glucose or intramuscular glucagon is required to reverse the hypoglycemia. Another frequent side effect of insulin therapy is weight gain. Some is due to increased caloric storage of glucose by insulin, and some is due to renal sodium retention resulting in fluid retention and edema. These effects can synergize with oral agents that are often coad-ministered with insulin, particularly sulfonylureas and thiazolidinediones. Other complications...

Metabolic alterations in Type 2 diabetes

The plasma glucose concentration in Type 2 diabetes varies according to the severity of the condition, but if a patient neglects his or her treatment and then attends a diabetic clinic, it would not be uncommon to find a plasma glucose concentration of 20 mmol l. The plasma glucose concentration is consistently raised throughout the day (Fig. 10.4), with an exaggerated response to meals. This highlights the important role of insulin in minimising the postprandial 'excursions' in plasma glucose concentration, which is impaired in Type 2 diabetes. In addition, plasma non-esterified fatty acid concentrations may be elevated throughout the day (Fig. 10.5). This elevation of plasma non-esterified fatty acid concentration may aggravate a number of features of the condition, reducing further the ability of insulin to stimulate glucose uptake by skeletal muscle and promoting hepatic VLDL-triacylglycerol secretion. Fig. 10.4 Twenty-four-hour profiles of plasma glucose concentration in...

Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

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