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Clinical Gems

Our clinical gems come from the top selling medical books, and text books because knowledge is everything when it comes to diabetes.

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #149: Glucose Toxicity Part 5

The effects are consistent with a role for O-GlcNAc in damping acute hormone- and phosphorylation-mediated signals in situations of chronic nutrient excess. Although discovered in the context of diabetes, the aforementioned changes mediated by the HBP can also be viewed as adaptive responses to excess nutrient flux: muscle cells protect themselves from excess glucose fluxes and the excess nutrients are eventually stored as fat. Indeed, if insulin signaling were not dampened and glycogen synthesis were effectively engaged even with overeating, a pound of ingested carbohydrate would result in approximately four pounds of hydrated glycogen in muscle, and it is easy to visualize diets rich in sodas and donuts resulting in the development of glycogen storage diseases.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #148: Glucose Toxicity Part 4

The hexosamine/O-linked N-acetyl glucosamine pathway: One metabolic fate of glucose is the hexosamine biosynthetic pathway (HBP), and high flux through this pathway, such as occurs in diabetes or overnutrition, has been convincingly linked to insulin resistance and beta-cell failure. In this pathway a relatively small fraction of cellular glucose flux—a few percent in most tissues—is converted to UDP-N-acetylglucosamine (UDP-GlcNAc) and other amino sugars. The rate limiting step is catalyzed by the enzyme glutamine: fructose-6-phosphate amidotransferase (GFA) that catalyzes the synthesis of glucosamine-6-P from fructose-6-P and glutamine.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #147: Glucose Toxicity Part 3

Chronic hyperglycemia as a cause of impaired insulin secretion In 1948, Lukens and Dohan administered large doses of glucose to normal cats and induced permanent hyperglycemia, hydropic degeneration of the islet of Langerhans, and ketonuria in 4 out of 35 cats studied. These investigators proposed that hyperglycemia could play a role in the pathogenesis of diabetes. In recent years, several approaches have been used to directly examine the harmful effects of chronic hyperglycemia on insulin secretion. These studies have established that chronic hyperglycemia impairs beta-cell responsiveness to glucose although the exact biochemical mechanism(s) mediating this effect remain to be clearly defined.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #146: Glucose Toxicity Part 2

Chronic hyperglycemia as a cause of insulin Resistance: Insulin resistance in patients with type 1 diabetes—a consequence of glucose toxicity? Insulin resistance both precedes and predicts type 2 diabetes and therefore is not merely due to hyperglycemia. In the case of type 1 diabetes, it is clear that insulin resistance is an acquired and reversible phenomenon since insulin sensitivity is completely normalized during remission of the disease.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #145: Glucose Toxicity Part 1

Several studies, culminating in the large and definitive Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have established that hyperglycemia is the major risk factor for microvascular diabetic complications. Chronic hyperglycemia also seems to be a significant and independent, albeit weaker risk factor for macrovascular disease. Other adverse consequences of hyperglycemia include an increased susceptibility to infections.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #144: The Genetics of Type 2 Diabetes Part 6

Gene–gene and gene–environment interactions: Gene–gene interactions, or epistasis, have been suggested as a possible explanation for difficulties in replicating genetic association in complex diseases. The standard statistical methods used in association studies are usually limited to analysis of single marker effects and thereby do not account for interactions between markers. Previous attempts to study epistasis in complex diseases have focused on interactions between candidate regions. However, the recent abundance of GWAS data has made a comprehensive search across the genome more feasible.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #143: The Genetics of Type 2 Diabetes Part 5

In spite of the large number of risk variants identified, it is estimated that they explain less than 15% of the heritability of T2DM. The unexplained heritability is an intensely discussed topic in complex genetics, some claiming it as a failure of GWA studies.There are many possible explanations for the missing heritability, including assumptions made about the genetic architecture of the disease and the definitions of heritability.The estimations of heritability explained assumes that only additive affects determine disease risk and that the risk follows the liability threshold model, that is, the genetic and environmental effects sum up to form a normal distribution of liability and that disease arises in individuals surpassing a certain threshold in the distribution [58]. If these assumptions are not true, the estimate of heritability explained will not be correct. However, there are also many other potential explanations for the missing heritability: yet unmapped common variants, distorted parent-of-origin transmission of risk alleles, rare variants, structural polymorphisms (e.g. copy number variations), gene–gene and/or gene–environment interactions (in which epigenetic effects may be important).

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #142: The Genetics of Type 2 Diabetes Part 4

High density mapping: GWAS do not inevitably lead to identification of a gene or genes in a given locus associated with disease.The most strongly associated SNPs are often only markers for the functional variant responsible for the observed genetic effect and most associated regions harbor several genes. Therefore, additional fine mapping of the loci in even larger sample sets is often necessary. To do this cost-efficiently a Cardio-Metabochip has been developed for metabolic/cardiovascular gene mapping. This custom-design Illumina Infinium genotyping chip contains ∼200,000 polymorphisms selected to cover association signals from a wide range of metabolic disorders (T2DM, lipid disorders, obesity, and cardiovascular disease), was designed to perform both deep replication of major disease signals and fine mapping of established loci. Meta-analysis of previous GWAS with an additional 22,669 T2DM cases and 58,119 controls genotyped using the Cardio-Metabochip has recently added another eight new loci associated with T2DM in the European population

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #141: The Genetics of Type 2 Diabetes Part 3

Identification of T2DM affecting genetic variants: The methods used to map disease-causing variation have evolved rapidly in the last decades thanks to technical advances in genotyping methods. Originally, disease-causing loci were identified primarily by linkage analysis, utilizing the long stretches of linkage in affected families. By genotyping 400–500 genetic markers, disease loci can be mapped on a genome-wide level without any prior hypothesis about which genes are involved. Finding that affected family members share a certain marker that is identical by descent (i.e., identical because it was inherited from the same parent) more often than expected by chance is evidence that a disease-causing variant is in linkage with that marker. This strategy has been very successful in mapping genetic diseases like MODY that have a strong penetrance and a known mode of inheritance.

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