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GLUCOSE HOMEOSTASIS

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DIABETES MELLITUS (DM)

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A heterogeneous group of disorders characterized by fasting and postprandial hyperglycemia that affects 1.8 per 1000 children under 20 years of age.

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EPIDEMIOLOGY

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  • Type 1 DM: Onset is usually in childhood, but may occur at any age; accounts for 85% of diabetes cases in children

  • Type 2 DM: Most prevalent in obese children during puberty; more frequent in African Americans, Hispanics, Pacific Islanders, Asians, and Pima Indians; accounts for 12% of diabetes cases in children

  • Maturity Onset Diabetes of the Young (MODY): Autosomal dominant inheritance; onset usually between 9 and 25 years of age; accounts for 1–2% of diabetes cases in children

  • Neonatal Diabetes: Spontaneous or inherited; onset usually <6 months of age; accounts for 1% of diabetes cases in children

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ETIOLOGY

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  • Type 1 DM: Autoimmune-mediated destruction of β-cells in predisposed individuals (certain HLA haplotypes), trigger(s) unknown

  • Type 2 DM: Progressive insulin secretory defect on the background of insulin resistance

  • MODY: Genetic defects in enzymes or nuclear transcription factors involved in the regulation of insulin secretion or pancreatic islet development

  • Neonatal Diabetes: Genetic defects in KATP channel, insulin, or transcriptions factors involved in the regulation of insulin secretion or in pancreatic/islet development

  • Other: Pancreatectomy, exocrine pancreatic disease (cystic fibrosis, hemochromatosis); other endocrinopathies (acromegaly, Cushing disease, pheochromocytoma); medications (glucocorticoids, β-blockers, phenytoin, asparaginase, cyclosporine, tacrolimus, vacor, pentamidine, diazoxide, nicotinic acid, thiazides); infections (cytomegalovirus, congenital rubella); genetic syndromes (Prader–Willi, Trisomy 21, Turner, Klinefelter)

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PATHOPHYSIOLOGY

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  • Insulin deficiency and/or impaired insulin action results in the abnormal metabolism of carbohydrate, protein, and fat

  • Type 1 DM: Destruction of pancreatic β-cells leads to absolute insulin deficiency. Lack of insulin results in excessive hepatic glucose production and impaired glucose utilization in muscle and fat leading to hyperglycemia, glycosuria, and an osmotic diuresis. Lipolysis and impaired lipid synthesis lead to elevated lipids, cholesterol, triglycerides, and free fatty acids, which are converted into ketones. Impaired utilization of glucose, excessive caloric and water losses in urine, and increasing catabolism all lead to weight loss

  • Type 2 DM: Insulin resistance and inadequate insulin secretion result in relative insulin deficiency. Most patients have sufficient insulin to suppress lipolysis and ketogenesis

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CLINICAL MANIFESTATIONS

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  • Type 1 DM: Polyuria, polydipsia, polyphagia, weight loss, fatigue, weakness, blurred vision, increased risk of infection; frequently presents with ketosis with or without acidosis

  • Type 2 DM: Overweight or obese; acanthosis nigricans (velvety hyperpigmented patches in skin folds of neck and axillae); may not present with polyuria, weight loss, ketosis, or diabetic ketoacidosis (DKA); may already have long-term complications at diagnosis

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DIAGNOSTICS

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  • Criteria for Diagnosis of DM: Random plasma glucose ≥200 mg/dL, or fasting plasma glucose ≥126 mg/dL, or hemoglobin A1c (HbA1c) ≥6.5% (all in the presence of symptoms of diabetes or on 2 separate days), or 2-hour plasma glucose ≥200 mg/dL during oral glucose tolerance test using a glucose load ...

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