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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 #151: Monogenic Disorders of the Beta Cell Part 1

This chapter will concentrate on the monogenic disorders of the beta cell that account for 1–2% of diabetes. They are discrete disorders, which are a significant cause of diabetes in their own right. Correct molecular diagnosis is important to predict clinical course, explain other associated clinical features, enable genetic counseling, diagnose family members, and most importantly guide appropriate treatment. In addition to this clinical importance, the discovery and study of monogenic disorders has given further insight into the physiology and pathophysiology of the beta cell.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #150: Glucose Toxicity Part 6

Clinical significance of glucose toxicity: After diagnosis of type 1 diabetes, initiation of insulin therapy induces partial clinical remission in ∼30% of the patients during the first year. This honeymoon period is characterized by normoglycemia, recovery of endogenous insulin secretion, and by improved insulin sensitivity. Although correction of several alterations secondary to insulin deficiency, such as increased counterregulatory hormone secretion, hyperosmolarity, acidosis, electrolyte changes and high free fatty acids could contribute to normalization of insulin secretion and sensitivity, reversal of glucose toxicity may also be of importance for the occurrence of remission.

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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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