{
 "topic": "Insulin Resistance",
 "slug": "insulin-resistance",
 "category_id": 15514,
 "passage_count": 14,
 "source_chars": 12972,
 "enough_material": true,
 "references": [
  {
   "title": "MedStudy Pediatrics Core 11th Edition 2024-2025",
   "author": null,
   "pages": [
    664
   ]
  },
  {
   "title": "Pediatric Clinical Practice Guidelines & Policies, 18th Edition",
   "author": "American Academy of Pediatrics",
   "pages": [
    915
   ]
  },
  {
   "title": "Ghai Essential Pediatrics, 9e (Vinod K Paul, Arvind Bagga)",
   "author": "CamScanner",
   "pages": [
    548
   ]
  },
  {
   "title": "Pediatric Dentistry: Infancy through Adolescence - Arthur J. Nowak, John R. Christensen, Tad R. Mabry, Janice A. Townsend, Martha H. Wells - 6th Edition (2018) 656 pp., ISBN: 978-0-323-60826-8",
   "author": "Arthur J. Nowak, John R. Christensen, Tad R. Mabry, Janice A. Townsend, Martha H. Wells",
   "pages": [
    191
   ]
  },
  {
   "title": "Pediatric Nutrition (Ronald E. Kleinman, Frank R. Greer)",
   "author": null,
   "pages": [
    1038
   ]
  },
  {
   "title": "Netters Pediatrics (Florin \u0422., Ludwig St.)",
   "author": null,
   "pages": [
    475
   ]
  },
  {
   "title": "Berkowitz's Pediatrics",
   "author": "Berkowitz, Carol D.;",
   "pages": [
    1174,
    1184
   ]
  },
  {
   "title": "Algorithms in Pediatrics",
   "author": null,
   "pages": [
    569
   ]
  }
 ],
 "passages": [
  {
   "source": "MedStudy Pediatrics Core 11th Edition 2024-2025, p. 664",
   "text": "insulin resistance. The insulin resistance is usually caused by mutation or dele- tion of both insulin receptor genes. Serum insulin levels are 100x normal and result in significant acanthosis nigricans. Most of these patients die before 1 year of age. Figure 15-43 shows Figure 15-43: Donohue achild with Donohue syn- syndrome; note facial features drome; note acanthosis in and low-set ears the axilla. HYPOGLYCEMIA PREVIEW | REVIEW \u00a9 Which tests are used to differentiate hypoglyce- mia due to exogenous administration of insulin from that due to endogenous production of insulin? Clinical hypoglycemia is defined as a plasma glucose concentration low enough to cause signs or symptoms of impaired brain function. Thresholds for signs and symptoms of hypoglycemia occur across a range of glucose levels and are influenced by availability of alter- nate fuels, such as ketones. In normal newborn infants, plasma glucose is initially maintained at ~ 55-65 mg/dL"
  },
  {
   "source": "Pediatric Clinical Practice Guidelines & Policies, 18th Edition, p. 915",
   "text": "**SECTION 4/2017 POLICIES** **896** treat children and adolescents who have insulin resistance with normal glucose concentrations. Although some studies have revealed beneficial effects of metformin on BMI and homeostatic model assessment of insulin resistance score in adolescents with insulin resistance, these trials were only 6 months in length and involved small numbers of subjects.[87] Thus, metformin is not currently recommended for treatment of insulin resistance.[70] No consensus exists in the pediatric diabetes community as to treatment of prediabetes in children, other than lifestyle management. Children found to have prediabetes or type 2 diabetes mellitus on screening can be referred to a pediatric endocrinologist for management and/ or monitoring.[88] It is also critical to screen for and address any comorbid conditions, such as PCOS or OSA, which often share the causal link of insulin resistance with MetS component risk factors. ## **suMMary**"
  },
  {
   "source": "Ghai Essential Pediatrics, 9e (Vinod K Paul, Arvind Bagga), p. 548",
   "text": "measurements done at 0 and 120 minutes. Insulin resistance with relative insulin deficiency: 10-50% of diabetes in adolescents depending on ethnicity served. Classification Ill. Other specific types of diabetes Reduced levels of action of insulin cause diabetes. Most 1. Genetic defects of beta cell function: Maturity onset children with diabetes have type 1 diabetes caused by diabetes of the young (MODY), neonatal diabetes, damage to beta cells of pancreas (Table 18.38). Type 2 MmltoenondHal dignrclers diabetes is an important cause in obese adolescents. Other 2. Genetic defects in insulin action: Insulin receptor defects, forms of childhood diabetes include genetic forms of lipodystrophy, type A insulin resistance, Rabson- diabetes (monogenic diabetes of young, MODY) and Mendenhall syndrome neonatal diabetes. 3. Diseases of exocrine pancreas: Pancreatitis, trauma/ In most situations, the type of diabetes is evident on pancreatectomy, cystic fibrosis, fibrocalcific pancreatic"
  },
  {
   "source": "Pediatric Dentistry: Infancy through Adolescence - Arthur J. Nowak, John R. Christensen, Tad R. Mabry, Janice A. Townsend, Martha H. Wells - 6th Edition (2018) 656 pp., ISBN: 978-0-323-60826-8, p. 191",
   "text": "## **Diabetic Emergencies** Diabetes mellitus is a disease involving insulin production and/or resistance.[94] Decreased insulin or insulin insensitivity leads to impairments in carbohydrate, fat, and protein metabolism. This disorder is characterized by hyperglycemia when left untreated.[95] Chronic hyperglycemia predisposes to vascular compromise with subsequent dysfunction of the cardiovascular system, peripheral nervous system, kidneys, and other body systems.[1,94] Type 1 or insulin-dependent diabetes mellitus occurs most commonly in children.[96] It results from loss of pancreatic \u03b2 cell function, which produces endogenous insulin.[1,95] Therefore, exogenous insulin is required by daily parenteral administration to control blood glucose levels.[1,95]"
  },
  {
   "source": "Pediatric Nutrition (Ronald E. Kleinman, Frank R. Greer), p. 1038",
   "text": "The etiology of insulin resistance is multifactorial and has been linked to both PI and nucleoside/nucleotide reverse transcriptase inhibitors (NNRTI or NRTI), used as monotherapy or in combination. Specific mechanisms have not been well defined. A study by Beregszaszi et al demonstrated that insulin resistance occurs at the level of the adipose tissue, and children with lipodystrophy have more pronounced insulin resistance than those without, suggesting that metabolic changes occur as a result of the central adiposity.[140] A possible mechanism by which HAART causes insulin resistance is by direct inhibition of the transport function of the GLUT4 glucose transporter, which is responsible for insulin-stimulated glucose uptake into muscle and fat.[141] Inflammatory cytokines have been linked to insulin resistance and diminished adiponectin, which affects insulin signaling and glucose homeostasis. Adipose tissue is a major determinant of insulin sensitivity, and changes associated with lipodystrophy can alter"
  },
  {
   "source": "Netters Pediatrics (Florin \u0422., Ludwig St.), p. 475",
   "text": "## **Box 72-1** Differential Diagnosis of Hypoglycemia in Infants and Children - Infant of a diabetic mother - Prolonged neonatal hypoglycemia - Perinatal stress-induced hyperinsulinism - Permanent hypoglycemia - Congenital hyperinsulinism - KATP channel hyperinsulinism - GDH hyperinsulinism - Glucokinase hyperinsulinism - SCHAD deficiency hyperinsulinism - Exercise-induced hyperinsulinism - Insulinoma - Other causes of hyperinsulinism - HN4-alpha mutations associated with familial monogenic diabetes - Factitious hyperinsulinism - Beckwith-Wiedemann syndrome - Anti-insulin and insulin receptor-stimulating antibodies - Congenital disorders of glycosylation - PPH (dumping syndrome) - Disorders of gluconeogenesis - GSD 1a - GSD 1b - F-1,6-Pase deficiency - Pyruvate carboxylase deficiency - Disorders of glycogen storage - GSD 0 - GSD 3 - GSD 6 - GSD 9 - Disorders of fatty acid oxidation - Pituitary hormone deficiency"
  },
  {
   "source": "Berkowitz's Pediatrics, p. 1184",
   "text": "6. What is the role of \u201ctight glycemic control\u201d in children and adolescents? Diabetes mellitus is the second most common chronic illness after asthma among children in developed countries. Diabetes mellitus is a metabolic imbalance that results from insulin deficiency, impairment of insulin action, or both. Advancement in the knowledge of the pathophysiology supports the assessment that diabetes is a heterogeneous disease involving immunologic, environmental, and genetic factors. This has led to a categorization of diabetes based on its pathophysiology rather than the therapeutic intervention. Diabetes associated with absolute insulin deficiency and impaired beta cell function is called type 1 (DM1) (previously juvenile onset or insulin-dependent), and diabetes associated with insulin resistance as well as impaired beta cell function is called type 2 (DM2) (previously adult onset or non-insulin-dependent)."
  },
  {
   "source": "Algorithms in Pediatrics, p. 569",
   "text": "**Box 2: Etiology of persistent hypoglycemia in newborns, infants, and children Hyperinsulinism** \u2022 Congenital hyperinsulinism { ABCC8, KCNJ11, GDH, glucokinase, HADH, HNF4 a , HNF1 a , SLC16A1, UCP2, PGM1, HK1 { Syndromic: Beckwith-Wiedemann, trisomy 13, Kabuki, and Costello syndromes \u2022 Insulinoma (sporadic or MEN1 associated) \u2022 Dumping syndrome \u2022 Exogenous insulin administration \u2022 Sulfonylurea ingestion **Hormone deficiencies** \u2022 Adrenocorticotropic hormone/cortisol deficiency \u2022 Growth hormone deficiency \u2022 Catecholamine deficiency (rare as isolated entity) **Carbohydrate disorders** \u2022 Glycogen storage diseases \u2022 Galactosemia \u2022 Hereditary fructose intolerance \u2022 Other disorders of gluconeogenesis **Fatty acid disorders** \u2022 Carnitine transporter deficiency \u2022 Carnitine palmitoyltransferase-1/2 deficiency \u2022 Carnitine translocase deficiency Very long/long/medium/short chain acyl-coenzyme A dehydrogenase deficiency **Amino acid disorders** \u2022 Methylmalonic acidemia \u2022 3-hydroxy-3-methylglutaric aciduria \u2022 Maple"
  },
  {
   "source": "Kliegman R. Nelson Textbook of Pediatrics 2-Volume Set 22ed 2024, p. 928",
   "text": "The initial treatment for dyslipidemia in a child always begins with a 6- month trial of lifestyle modification, namely, improvements in dietary and physical activity patterns. Being overweight confers a special risk of CVD because of the strong association with insulin resistance syndrome (metabolic syndrome). Although there is no standardized definition of metabolic syndrome for youth, it is likely that half of all severely obese children are insulin resistant. Data from the CARDIAC project noted that 49% of fifth- grade children with the hyperpigmented rash, acanthosis nigricans, had three or more factors for insulin resistance syndrome when using the definition classically used for adults, including evidence of insulin resistance, hypertension, HDL- C <40 mg/dL, and triglycerides >150 mg/dL, in addition to obesity."
  },
  {
   "source": "Berkowitz's Pediatrics, p. 1174",
   "text": "Glucose intolerance may occur in some children with CKD despite elevated insulin levels. This may occur independently or in association with genetic diseases, such as hepatocyte nuclear factor-1b mutations, which induce renal cysts and atypical diabetes mellitus. The linear correlation between a decline in renal function and insulin resistance even at the early stages of CKD has been shown in adults. More than 50% of children develop hyperlipidemia by the time they reach ESRD. The characteristic plasma lipid abnormality is a moderate hypertriglyceridemia. A high prevalence of hypercholesterolemia and low levels of high-density lipids and albumin are characteristic as well. These derangements have a role in the manifestation of cardiovascular disease. ## **Growth Failure**"
  },
  {
   "source": "Cover, p. 8250",
   "text": "and intrauterine growth retardation. These children rarely survive infancy. Rabson-Mendenhall also is caused by defects in the insulin receptor gene and is diagnosed in infancy, with extreme growth retardation, marked insulin resistance, and diabetes. Type 1 insulin resistance, due to a usually recessive defect in the insulin receptor, is diagnosed in adolescence, with diabetes, insulin resistance, polycystic ovaries, and other manifestations of androgen excess in the absence of obesity. Lipodystrophy is characterized by partial or total loss of subcutaneous fat, polycystic ovarian syndrome, elevated insulin levels, and diabetes. The total form is caused by a recessive mutation in _Seipin_ and the _AGPAT2_ gene and the partial form by a dominant mutation in the _lamin AC_ and _PPARG_ genes. ## **Diseases Originating in the Exocrine Pancreas**"
  },
  {
   "source": "MedStudy Pediatrics Core 11th Edition 2024-2025, p. 664",
   "text": "of MODY. MODY 1 and MODY 3 are more severe than MODY 2. Many patients with MODY respond to sulfonylureas and do not require insulin therapy. Sulfonylurea therapy is 1\u00b0 line therapy (only time in a child) for those with MODY 1 and MODY 3. MODY 2 does not require treat- ment in childhood, because children have persistent mild-fasting hyperglycemia, normal response to car- bohydrate ingestion, and low rates of development of complications. (Essentially, they have a higher glucose set-point for insulin secretion.) INSULIN RESISTANCE SYNDROMES These are a spectrum of syndromes that result from either a homozygous or heterozygous mutation in the INSR (insulin receptor) gene on chromosome 19. We will discuss the most severe form here. Donohue syndrome (a.ka. leprechaunism) is a rare syndrome of intrauterine growth restriction, fasting hypoglycemia, and post- prandial hyperglycemia in association with profound insulin resistance. The insulin resistance is usually caused by mutation or dele-"
  },
  {
   "source": "Kliegman R. Nelson Textbook of Pediatrics 2-Volume Set 22ed 2024, p. 4151",
   "text": "Fig. 698.14 Velvety hyperpigmentation of the axilla in acanthosis nigricans. is inherited as an autosomal dominant trait and develops in infancy. Insulin resistance with compensatory hyperinsulinism may lead to insulin binding to and activation of insulin- like growth factor receptors, promoting epidermal and fibroblast growth. Common causes of insulin resistance in children are obesity and diabetes mellitus, with acanthosis nigricans seen in >60% of children with a body mass index >98%. Other endocrinopathies such as pituitary hypogonadism, Cushing syndrome, polycystic ovarian syndromes, thyroid disease, and acromegaly, as well as certain drugs (insulin, oral contraceptives and other sex hormones, nicotinic acid, corticosteroids, and heroin) are also implicated as potential underlying causes. In the paraneoplastic form (rare in children), tumor- secreted growth factors induce acanthosis nigricans. ## **CLINICAL MANIFESTATIONS**"
  },
  {
   "source": "Kliegman R. Nelson Textbook of Pediatrics 2-Volume Set 22ed 2024, p. 3584",
   "text": "## **GENETIC DEFECTS OF INSULIN ACTION** Various genetic variants in the insulin receptor can impair the action of insulin at the insulin receptor or impair postreceptor signaling, leading to insulin resistance. The mildest form of the syndrome with variants in the insulin receptor was previously known as **type A insulin resistance** . This condition is associated with hirsutism, hyperandrogenism, and cystic ovaries in females, without obesity. Acanthosis nigricans may be present, and life expectancy is not significantly impaired. More severe forms of insulin resistance are seen in two variants in the insulin receptor gene that cause the pediatric syndromes of **Donohue syndrome** (formerly called _leprechaunism_ ) and **Rabson- Mendenhall syndrome** . ## **Donohue Syndrome** This is a syndrome characterized by intrauterine growth restriction, fasting hypoglycemia, and postprandial hyperglycemia in association with profound resistance to insulin; severe hyperinsulinemia is seen"
  }
 ]
}