Insulin deficiency

Insulin is a powerful anabolic hormone but it is unlikely that insulin deficiency causes skeletal muscle atrophy by direct action on muscle fibers (as opposed to neurogenic atrophy) except in chronic untreated cases. There is however a close parallel between the catabolic states induced by glucocorticoid excess and by insulin deficiency. Moreover, impaired insulin action is implicated in other endocrine myopathies as a contributory cause of muscle wasting. Both acromegaly and thyrotoxicosis are associated with insulin resistance due to a postreceptor defect, and secondary hyperparathyroidism due to hypophosphatemia also gives rise to insulin insensitivity. 

CF-related diabetes shares characteristics of both type 1 and type 2 diabetes mellitus but is categorized separately. The primary cause of CFRD is insulin deficiency resulting from both reduced functional pancreatic islet cells and increased islet amyloid deposition. Insulin secretion is delayed in response to glucose challenge, and absolute insulin secretion over time is reduced. Some insulin resistance may also be present in CFRD however, sensitivity may be increased in CF patients without diabetes.8... 

Type 2 DM is the most prevalent form of diabetes and accounts for approximately 90% to 95% of all diagnosed cases. Type 2 DM is usually slow and progressive in its development and often is preceded by pre-diabetes. Rising blood glucose levels result from increasing insulin resistance and impaired insulin secretion leading to a situation of relative insulin deficiency. 

In overweight adults, a diabetic metabolic condition may develop (type II or non-insuUn-dependent diabetes) when there is a relative insulin deficiency-enhanced demand cannot be met by a diminishing insulin secretion. The cause of increased insulin requirement is a loss of insulin receptors or an impairment of the signal cascade activated by the insulin receptor. Accordingly, insulin sensitivity of cells declines. This can be illustrated by comparing concentration-binding curves in cells from normal and obese individuals... 

Diabetes mellitus is a very common metabolic disease that is caused by absolute or relative insulin deficiency. The lack of this peptide hormone (see p. 76) mainly affects carbohydrate and lipid metabolism. Diabetes mellitus occurs in two forms. In type 1 diabetes (insulin-dependent diabetes mellitus, IDDM), the insulin-forming cells are destroyed in young individuals by an autoimmune reaction. The less severe type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM) usually has its first onset in elderly individuals. The causes have not yet been explained in detail in this type. 

The increased degradation of fat that occurs in insulin deficiency also has serious effects. Some of the fatty acids that accumulate in large quantities are taken up by the liver and used for lipoprotein synthesis (hyperlipidemia), and the rest are broken down into acetyl CoA. As the tricarboxylic acid cycle is not capable of taking up such large quantities of acetyl CoA, the excess is used to form ketone bodies (acetoacetate and p-hydroxy-butyrate see p. 312). As H"" ions are released in this process, diabetics not receiving adequate treatment can suffer severe metabolic acidosis (diabetic coma). The acetone that is also formed gives these patients breath a characteristic odor. In addition, large amounts of ketone body anions appear in the urine (ketonuria). 

This is immune-mediated pancreatic /3-cell destruction characterized by absolute insulin deficiency. 

Il.f.l.1. Insulins. Insulin is the most effective of diabetes medications. Insulin has profound effects on carbohydrate, protein, fat metabolism and electrolytes. It has anabolic and anticatabolic actions. In a state of insulin deficiency, glycogenesis, glucose transport, protein synthesis, triglyceride synthesis, LPL activity in adipose tissue, cellular potassium uptake all decrease on the other hand, gluconeogene-sis, glycogenolysis, protein degradation, ketogene-sis, lipolysis increase. 

Diabetes mellitus has been traditionally classified into insulin-dependent diabetes mellitus (IDDM), also known as type I (formerly called juvenile-onset diabetes mellitus), and non-insulin-dependent diabetes mellitus (NIDDM), also known as type II (formerly referred to as adult-onset diabetes mellitus). There are clearly varying degrees of overlap, and though it is often important to know whether a particular individual possesses relative insulin deficiency or relative insulin resistance or both, some of the more salient differences between IDDM and NIDDM are summarized in Table 67.1. 

The pathogenesis of type I diabetes is autoimmune destruction of the cells of the pancreas. The factor or factors that trigger this autoimmune response are unknown. Predisposing factors appear to include certain major histocompatibility complex haplotypes and autoantibodies to various islet cell antigens. The progression of the autoimmune response is characterized by lymphocytic infiltration and destruction of the pancreatic cells resulting in insulin deficiency. Type I diabetes mellitus constitutes about 10% of cases of diabetes mellitus. 

Treating Diabetes Mellitus. There are two main types of diabetes. Type I diabetes (previously called insulin-dependent diabetes mellitus, IDDM) is a severe form which occurs most commonly in juveniles and young adults and which results from an absolute insulin deficiency arising from pancreatic B cell destruction, presumably via an immune-mediated mechanism. Type II diabetes (previously called non-insulin-dependent diabetes mellitus, NIDDM) is a milder, heterogeneous form of diabetes which occurs more... 

In diabetes mellitus, there is either insulin deficiency or insulin resistance in peripheral tissues which lead to hyperglycemia and glycosuria. Insulin corrects the various abnormalities of carbohydrate metabolism by its action on various tissues. 

Over 5% of the population of western nations is afflicted with diabetes. TTie most prevalent form of diabetes, non-insulin-dependent diabetes mellitus (NIDDM, or type 11), is commonly associated with obesity and hypertension, and is believed to be the consequence of altered insulin action or insulin secretion (for review see Defronzo, 1988 Defronzo and Ferrannini, 1991). Insulin-dependent diabetes mellitus (IDDM, or type 1 diabetes) accounts for approximately 10% of all cases of diabetes. IDDM is characterized by specific destruction of insulin secreting /3-cells found in islets of Langerhans. Destruction of 80-90% of islet /3-cells causes insulin deficiency and the inability to regulate blood glucose levels. 

The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and severe or absolute insulin deficiency. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is the most common form of type 1 diabetes. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage, but only 10-15% of patients have a positive family history. 

Secondary growth hormone insensitivity syndrome is thought to develop when chronic insulin deficiency and poor metabolic control occur in people with type 1 diabetes. High growth hormone concentrations are found in conjunction with low concentrations of IGF1. 

A wide spectrum of thiazolidinedione compounds have been synthesized and characterized over the past 15 years. In general, these compounds were shown to be active in obese rodent models of type 2 diabetes but were not active in insulin-deficient diabetes, as in streptozo-tocin-treated rats. Thus, the compounds were shown to be insulin sensitizers with little or no potential to evoke hypoglycemia. In addition to potent insulin-sensitizing and glucose-lowering effects, the thiazolidinediones also showed substantial efficacy with respect to hypertriglyceridemia in animal models. A small number of thiazolidinediones have... 

A deficiency in insulin production results in a condition called diabetes mellitus. Approximately 6.2 percent of the population in the United States is affected with diabetes. Type 1 diabetics account for 10 percent of those individuals suffering from diabetes mellitus. It is also known as juvenile diabetes and generally develops in young people, typically between the ages of ten and fifteen years, as a result of an autoimmune disorder. Why the body s immune system turns on itself, attacking and destroying beta cells, the pancreatic cells in which insulin is synthesized, is not clear. The unfortunate consequence is insulin deficiency. 

Avogaro, A., Nosadini, R., Doria, A., Fioretto, P., Velussi, M., Vigorito, C., Sacca, L., Toffolo, G., Cobelli, C., Trevisan, R., et al. 1990. Myocardial metabolism in insulin-deficient diabetic humans without coronary artery disease. Am J Physiol 258(4 Pt 1) E606-E618. 

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