Type-2 diabetes

Diabetes mellitus is apparently not a single, homogeneous disease but rather a disease existing in at least two primary forms.35 90 Patients with diabetes mellitus are usually classified as having either type 1 or type 2 diabetes, depending on the disease pathogenesis. The primary characteristics of type 1 and type 2 diabetes mellitus are summarized in Table 32-1. Specific aspects of these two primary forms of diabetes mellitus are discussed in more detail below. 

The exact cause of type 1 diabetes is unknown. There is considerable evidence, however, that the beta 

Type 2, also known previously as non-insulin-dependent diabetes mellitus (NIDDM), accounts for 90 to 95 percent of persons with diabetes mellitus.19 This form of diabetes usually occurs in adults, especially in older individuals.35,102 Type 2 diabetes, however, can also occur in young people, and there is concern that the incidence of this disease is increasing dramatically in children and adolescents.9,83 Although the specific factors responsible for this disease are unknown, a genetic predisposition combined with poor diet, obesity, and lack of exercise all seem to contribute to the onset of type 2 diabetes.50,81,83 Increased body weight is common in patients with type 2 diabetes. 

Whereas insulin cannot be produced in type 1 diabetes, the problem in type 2 diabetes is somewhat more complex.116 In most patients with type 2 diabetes, pancreatic beta cells remain intact and are capable of producing insulin. Therefore, the primary problem in type 2 diabetes is a decreased sensitivity of peripheral tissues to circulating insulin this is referred 

Finally, insulin resistance is present in disease states other than type 2 diabetes mellitus. Patients with conditions such as hypertension, obesity, and certain hyperlipidemias are also found to have decreased tissue sensitivity to circulating insulin.19,72 As discussed in Chapter 21, a combination of these abnormalities is often described as metabolic syndrome, or syndrome X.127,128 Metabolic syndrome occurs when insulin resistance, high blood pressure, abdominal 

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Silvetre, J. S., and Prous, J. (2005). Research on adverse drug events Muscarinic m3 receptor binding affinity could predict the risk of antipsycho tics to induce type 2 diabetes. Meth. Find. Exp. Clin. Pharmacol. 27 289-304. 

The wide range of inflammation-related factors that adipocytes secrete is linked to the inflammatory response that the tissue exhibits in obesity [1]. Obesity in general, like an increasing number of other diseases, is characterised by a state of mild chronic inflammation, and adipose tissue plays a central role in this. The production of most inflammation-related adipokines increases markedly in obesity and there is an elevated circulating level of a number of these factors as well as of other inflammatory markers such as C-reactive protein (CRP). The increased production of inflammatory adipokines (and decreased production of adiponectin with its anti-inflammatory action) in the obese is considered to play a critical role in the development of the obesity-associated pathologies, particularly type 2 diabetes and the metabolic syndrome [1]. 

Type 2 diabetes is a heterogeneous and progressive endocrine disorder associated with insulin resistance (impaired insulin action) and defective function of the insulin-secreting (3-cells in the pancreatic islets of Langerhans. These endocrine disorders give rise to widespread metabolic disturbances epitomised by hyperglycaemia. The present classes of antidiabetic agents other than insulin act to either increase insulin secretion, improve insulin action, slow the rate of intestinal... 

The incretin effect is reduced in type 2 diabetes, and this is attributed, at least in part, to reduced secretion of GLP-1. The biological actions of GLP-1 remain essentially intact in type 2 diabetes, but administration of extra GLP-1 is not a practical therapeutic option because the peptide is degraded rapidly if A < 2 min) by the enzyme dipeptidyl peptidase IV (DPP-4). DPP-4 cleaves the N-terminal dipeptide from many of the peptides that have either an alanine or a proline residue penultimate to the N-terminus (Fig. 6). 

Krentz AJ, Bailey CJ (2005) Oral antidiabetic agents current role in type 2 diabetes mellitus. Drags 65 385-411... 

Nathan DM, Buse JB, Davidson MB et al (2006) Management of hyperglycaemia in type 2 diabetes a consensus algorithm for the initiation and adjustment of therapy. Diabetologia 49 1711-1721... 

Schwanstecher C, Schwanstecher M (2002) Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes 51 (Suppl 3) S358-362... 

A class of drug derived from guanidine, including metformin and phenformin. Metformin is currently widely used in humans for the treatment of type 2 diabetes. Phenformin was formerly also widely used but was withdrawn because of problems with lactic acidosis. 

As described in the previous section, bile acids have evolved over the last years from regulators of bile acid homeostasis to general metabolic integrators. It is therefore not too surprizing that a number of bile acid-activated signaling pathways have become attractive targets for the treatment of gallstones and other metabolic diseases, such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis. 

Calpain-10 (CAPN10) is the fust diabetes gene to have been identified through a genome scan. The discovery of calpain-10 has identified it as a molecule of importance to insulin signaling and secretion that may have relevance to the fiiture development of novel therapeutic targets for the treatment of type 2 diabetes. 

Type 2 diabetes mellitus Mutations in intron 3 of Capn10 gene is associated with increased incidence of type 2 diabetes in some populations35... 

Diabetes mellitus is defined as hyperglycaemia (fasting > 7 mM and/or 2 h postprandial >11.1 mM) due to absolute or relative lack of insulin. The most common forms are type 1 diabetes (prevalence 0.25%), with absolute lack of insulin, and type 2 diabetes (prevalence 4-6%) which is due to the combination of insulin resistance and insufficient insulin secretion. 

Type 2 Diabetes (Previonsiy non-lnsnlin-Dependent Diabetes Mellitns, NIDDM)... 

Obesity and hyperglycemia 2. 2-AG levels are elevated in mouse adipocytes and epididymal of mice with DIO. AEA and 2-AG levels are elevated in rat insulinoma p-cells, in pancreas of mice with DIO, and in obese women. Patients with obesity or hyperglycaemia caused by type 2 diabetes exhibit elevated levels of 2-AG or of both endocannabinoids in visceral fat or blood, respectively. AEA levels are elevated in the liver of DIO mice 2. CB1 antagonists... 

Knockout mice have been reported for several FATPs [1]. As insulin desensitization has been closely linked to excessive fatty acid uptake and intracellular diacylgly-cerol and TG accumulation, these animal models were particularly evaluated in the context of protection from diet-induced type 2 diabetes ( Type 2 Diabetes Mellitus (T2DM)). In addition, studies on human subjects have also established genetic links between polymorphisms in FATP genes and metabolic alterations [1]. 

Withers DJ, White M (2000) Perspective the insulin signaling system - a common link in the pathogenesis of type 2 diabetes. Endocrinology 141 1917-1921... 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

PPARy White adipose tissue, atherosclerotic lesions Insulin-sensitizing and glucoselowering re-directs TG from non-adipose tissues and visceral adipose depots for storage in subcutaneous adipose tissue slowed progression of atherosclerosis Fatty acids, eico-sanoids Th iazolid i ned iones pioglitazone (Actos ), rosiglita-zone (Avandia ) Type 2 diabetes, (insulin resistance, metabolic syndrome)... 

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