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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 #159: Immunopathogenesis of Type 1 Diabetes in Western Society Part 2

Genetic predisposition is an important component of the multifactorial pathogenesis of T1DM. Although often diagnosed in individuals with no known family history of T1DM, the disease is about 15 times more common in siblings of a patient than in the general population. Siblings have an average risk of 6%, although individual risk varies significantly in relation to the extent of sharing predisposing genes with the proband, which allele variants are shared, and other factors. The risk to the offspring of affected mothers and fathers is about 2–3% and 6–7%, respectively. Among twins, the observed disease concordance rates are approximately 8–10% in dizygotic twins and, with extended follow-up, more than 60% in monozygotic twins.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #158: Immunopathogenesis of Type 1 Diabetes in Western Society Part 1

Introduction: Type 1 diabetes (T1DM), formerly referred to as insulin dependent diabetes mellitus (IDDM) and juvenile diabetes, is considered a chronic autoimmune disease. Over time, the disease process results in the virtually complete elimination of pancreatic beta cells and lifelong insulin deficiency. In turn, patients become dependent on daily insulin injections to maintain an acceptable level of metabolic control. It is widely accepted that T1DM is a complex, multifactorial disease in which genetic predisposition and environmental exposures promote the triggering of multiple autoimmune responses against beta cells.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #157: Monogenic Disorders of the Beta Cell Part 7

Maternally inherited diabetes and deafness (MIDD) most commonly results from heteroplasmic G to A substitution of the mitochondrial DNA at nucleotide pair 3243 in one of the two tRNA(Leu) genes. The same mutation that causes MIDD also causes a syndrome of severe neuromuscular disease called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke). Within a family there is usually a dominant phenotype, although occasionally some members develop MIDD whilst others develop MELAS.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #156: Monogenic Disorders of the Beta Cell Part 6

Renal cysts and diabetes (RCAD) syndrome: HNF1B-MODY
Molecular genetics of RCAD
HNF1B is a transcription factor with a role in regulating gene expression in a number of tissues. HNF1B forms homo and heterodimers with HNF1A, is present in similar tissues although at different levels, and binds to the same DNA consensus sequence. Despite these similarities HNF1B mutations cause diabetes by a different mechanism and have a distinct phenotype. There is autosomal dominant inheritance, although up to 50% of cases arise from de novo mutations or deletions.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #155: Monogenic Disorders of the Beta Cell Part 5

Neonatal diabetes (NDM) is defined as monogenic beta-cell diabetes which is diagnosed in the first six months of life. It is rare, affecting one in 200,000 live births. The evidence that a diagnosis before 6 months is the cut-off between monogenic neonatal diabetes rather than polygenic T1DM comes from studies of high-risk type 1 HLA, antibodies, birth weight (reduced before 6 months suggests a reduced insulin secretion in utero) and monogenic genetic studies.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #154: Monogenic Disorders of the Beta Cell Part 4

Transcription factor MODY: The majority of MODY genes encode transcription factors (TF). Transcription factors have an important role in regulating the expression of genes. They have a critical role in the variations in gene expression in the different stages of embryological development, and in different tissues. Transcription factors can also regulate expression of other transcription factors, thus establishing a complex regulatory network controlling gene expression.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #153: Monogenic Disorders of the Beta Cell Part 3

Glucokinase MODY: Glucokinase catalyzes the phosphorylation of glucose to glucose-6-phosphate. Its unique kinetic properties result in the rate of glucose phosphorylation being proportional to the physiologic glucose concentration. This means that the beta cell and hepatocyte can respond appropriately to fluctuations in the degree of glycemia. In the pancreatic beta cell, glucokinase acts as “the glucose sensor” ensuring insulin release is appropriate to the blood glucose concentration.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #152: Monogenic Disorders of the Beta Cell Part 2

Maturity-onset diabetes of the young (MODY) refers to group of monogenic subtypes of diabetes characterized by young onset (usually before 25 years) of non-insulin-dependent diabetes, beta-cell dysfunction that is inherited as an autosomal dominant trait. Mutations in at least 10 genes have been found to cause MODY; the common subtypes are due to mutations in GCK, Hepatocyte nuclear factor 1-alpha (HNF1A), HNF4A, and HNF1B. The definition of the underlying genes has resulted in the recognition of distinct clinical and physiologic subgroups of MODY with varying clinical course, prognosis, and treatment requirements. Classifications of diabetes by the ADA and the WHO recognize these discrete subtypes.

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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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