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Hyperinsulinemia

MedGen UID:
43779
Concept ID:
C0020459
Disease or Syndrome; Finding
Synonym: Hyperinsulinism
SNOMED CT: Hyperinsulinemia (83469008); Hyperinsulinism (83469008)
 
HPO: HP:0000842
Monarch Initiative: MONDO:0002177

Definition

An increased concentration of insulin in the blood. [from HPO]

Conditions with this feature

Prader-Willi syndrome
MedGen UID:
46057
Concept ID:
C0032897
Disease or Syndrome
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Leprechaunism syndrome
MedGen UID:
82708
Concept ID:
C0265344
Disease or Syndrome
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Alstrom syndrome
MedGen UID:
78675
Concept ID:
C0268425
Disease or Syndrome
Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.
Rabson-Mendenhall syndrome
MedGen UID:
78783
Concept ID:
C0271695
Disease or Syndrome
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Hyperproinsulinemia
MedGen UID:
137967
Concept ID:
C0342283
Disease or Syndrome
Insulin (INS; 176730) is produced posttranslationally from its precursor molecule, proinsulin, by site-directed proteolysis in beta-cell granules. Conversion involves cleavage at pairs of basic residues that link both the insulin A and B chains to C-peptide. Human proinsulin conversion has a preferred sequential route, such that cleavage at the B-chain/C-peptide junction occurs first, producing des-31,32 split proinsulin as the major conversion intermediate. Under normal circumstances, proinsulin conversion is largely completed before secretion, and low plasma levels of intact proinsulin and conversion intermediates are found. Structural abnormalities in the proinsulin molecule can impair conversion, leading to the accumulation of proinsulin-like material in the circulation. Such defects show an autosomal dominant mode of inheritance and are the main cause of familial hyperproinsulinemia (summary by Warren-Perry et al., 1997).
Familial partial lipodystrophy, Dunnigan type
MedGen UID:
354526
Concept ID:
C1720860
Disease or Syndrome
Familial partial lipodystrophy is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. Affected individuals gradually lose fat from the upper and lower extremities and the gluteal and truncal regions, resulting in a muscular appearance with prominent superficial veins. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently. Familial partial lipodystrophy may also be referred to as lipoatrophic diabetes mellitus, but the essential feature is loss of subcutaneous fat (review by Garg, 2004). The disorder may be misdiagnosed as Cushing disease (see 219080) (Kobberling and Dunnigan, 1986; Garg, 2004). Genetic Heterogeneity of Familial Partial Lipodystrophy Familial partial lipodystrophy is a clinically and genetically heterogeneous disorder. Types 1 and 2 were originally described as clinical subtypes: type 1 (FPLD1; 608600), characterized by loss of subcutaneous fat confined to the limbs (Kobberling et al., 1975), and FPLD2, characterized by loss of subcutaneous fat from the limbs and trunk (Dunnigan et al., 1974; Kobberling and Dunnigan, 1986). No genetic basis for FPLD1 has yet been delineated. FPLD3 (604367) is caused by mutation in the PPARG gene (601487) on chromosome 3p25; FPLD4 (613877) is caused by mutation in the PLIN1 gene (170290) on chromosome 15q26; FPLD5 (615238) is caused by mutation in the CIDEC gene (612120) on chromosome 3p25; FPLD6 (615980) is caused by mutation in the LIPE gene (151750) on chromosome 19q13; FPLD7 (606721) is caused by mutation in the CAV1 gene (601047) on chromosome 7q31; FPLD8 (620679), caused by mutation in the ADRA2A gene (104210) on chromosome 10q25; and FPLD9 (620683), caused by mutation in the PLAAT3 gene (613867) on chromosome 11q12.
PPARG-related familial partial lipodystrophy
MedGen UID:
328393
Concept ID:
C1720861
Disease or Syndrome
A rare familial partial lipodystrophy with characteristics of adult onset of distal lipoatrophy with gluteofemoral fat loss, as well as increased fat accumulation in the face and trunk and visceral adiposity. Additional manifestations include diabetes mellitus, atherogenic dyslipidemia, eyelid xanthelasma, arterial hypertension, cardiovascular disease, hepatic steatosis, acanthosis nigricans on axilla and neck, hirsutism, and muscular hypertrophy of the lower limbs. Caused by heterozygous mutation in the PPARG gene on chromosome 3p25.
Congenital generalized lipodystrophy type 1
MedGen UID:
318592
Concept ID:
C1720862
Disease or Syndrome
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.
Congenital generalized lipodystrophy type 2
MedGen UID:
318593
Concept ID:
C1720863
Congenital Abnormality
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.
Mandibuloacral dysplasia with type B lipodystrophy
MedGen UID:
332940
Concept ID:
C1837756
Disease or Syndrome
Mandibuloacral dysplasia with type B lipodystrophy (MADB) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies such as mandibular hypoplasia, skeletal anomalies such as progressive osteolysis of the terminal phalanges and clavicles, and skin changes such as mottled hyperpigmentation and atrophy. The lipodystrophy is characterized by generalized loss of subcutaneous fat involving the face, trunk, and extremities. Some patients have a progeroid appearance. Metabolic complications associated with insulin resistance have been reported (Schrander-Stumpel et al., 1992; summary by Simha et al., 2003). For a general phenotypic description of lipodystrophy associated with mandibuloacral dysplasia, see MADA (248370).
Homozygous 11P15-p14 deletion syndrome
MedGen UID:
338336
Concept ID:
C1847866
Disease or Syndrome
Exercise-induced hyperinsulinism
MedGen UID:
351246
Concept ID:
C1864902
Disease or Syndrome
The severity of congenital hyperinsulinism varies widely among affected individuals, even among members of the same family. About 60 percent of infants with this condition experience a hypoglycemic episode within the first month of life. Other affected children develop hypoglycemia by early childhood. Unlike typical episodes of hypoglycemia, which occur most often after periods without food (fasting) or after exercising, episodes of hypoglycemia in people with congenital hyperinsulinism can also occur after eating.\n\nCongenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin. Insulin is a hormone that helps control levels of blood glucose, also called blood sugar. People with this condition have frequent episodes of low blood glucose (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of low blood glucose increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.
Congenital generalized lipodystrophy type 4
MedGen UID:
412871
Concept ID:
C2750069
Disease or Syndrome
Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).
Estrogen resistance syndrome
MedGen UID:
815580
Concept ID:
C3809250
Disease or Syndrome
Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 19
MedGen UID:
1638030
Concept ID:
C4693522
Finding
Patients with biallelic mutations in the ADCY3 gene show hyperphagia within the first 2 years of life and develop severe obesity. Other features include hyposmia or anosmia, and some patients exhibit mild to moderate intellectual disability (Saeed et al., 2018).
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20
MedGen UID:
1674972
Concept ID:
C4759928
Finding
Obesity due to mutation in the MC4R gene is the most common cause of monogenic obesity. Patients have early-onset severe obesity and hyperphagia (Farooqi et al., 2003).
Mandibuloacral dysplasia with type A lipodystrophy
MedGen UID:
1757618
Concept ID:
C5399785
Disease or Syndrome
Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an autosomal recessive disorder characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes (Young et al., 1971; Simha and Garg, 2002; summary by Garavelli et al., 2009). See also MAD type B (MADB; 608612), which is caused by mutation in the ZMPSTE24 gene (606480).
BDV syndrome
MedGen UID:
1785671
Concept ID:
C5543403
Disease or Syndrome
BDV syndrome (BDVS) is an autosomal recessive disorder characterized by early-onset profound obesity, hyperphagia, and moderately impaired intellectual development accompanied by infantile hypotonia and other endocrine disorders including hypogonadotropic hypogonadism, hypothyroidism, and insulin resistance (summary by Bosch et al., 2021).
Atelis syndrome 2
MedGen UID:
1824055
Concept ID:
C5774282
Disease or Syndrome
Atelis syndrome-2 (ATELS2) is an autosomal recessive disorder characterized by poor overall growth with microcephaly and short stature, dysmorphic facial features, and congenital cardiac defects. Additional more variable features may include hematologic abnormalities, variable ocular abnormalities, motor delay, and anxiety. Patient cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy (Grange et al., 2022). See also ATELS1 (620184), caused by mutation in the SLF2 gene (610348). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).
Obesity and hypopigmentation
MedGen UID:
1824062
Concept ID:
C5774289
Disease or Syndrome
Obesity and hypopigmentation (OBHP) is characterized by early-onset severe obesity and hypopigmentation of the skin. Some affected individuals have red hair, and some experience increased appetite and exhibit reduced energy expenditure (Kempf et al., 2022).
Hyperinsulinemic hypoglycemia, familial, 8
MedGen UID:
1824072
Concept ID:
C5774299
Disease or Syndrome
Familial hyperinsulinemic hypoglycemia-8 (HHF8) is an autosomal recessive disorder characterized by protein-related hypoglycemia and persistent mild hyperammonemia (summary by Shahroor et al., 2022). For a phenotypic description and a discussion of genetic heterogeneity of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).

Professional guidelines

PubMed

Nakamura K, Miyoshi T, Yoshida M, Akagi S, Saito Y, Ejiri K, Matsuo N, Ichikawa K, Iwasaki K, Naito T, Namba Y, Yoshida M, Sugiyama H, Ito H
Int J Mol Sci 2022 Mar 25;23(7) doi: 10.3390/ijms23073587. PMID: 35408946Free PMC Article
Park JJ
Diabetes Metab J 2021 Mar;45(2):146-157. Epub 2021 Mar 25 doi: 10.4093/dmj.2020.0282. PMID: 33813813Free PMC Article
Leisegang K, Sengupta P, Agarwal A, Henkel R
Andrologia 2021 Feb;53(1):e13617. Epub 2020 May 12 doi: 10.1111/and.13617. PMID: 32399992

Recent clinical studies

Etiology

Acevedo-Fernández M, Porchia LM, Elguezabal-Rodelo RG, López-Bayghen E, Gonzalez-Mejia ME
Nutr Metab Cardiovasc Dis 2023 Sep;33(9):1725-1732. Epub 2023 May 24 doi: 10.1016/j.numecd.2023.05.023. PMID: 37407310
Love KM, Liu Z
J Clin Endocrinol Metab 2021 May 13;106(6):1553-1565. doi: 10.1210/clinem/dgab078. PMID: 33570554Free PMC Article
Kolb H, Kempf K, Röhling M, Martin S
BMC Med 2020 Aug 21;18(1):224. doi: 10.1186/s12916-020-01688-6. PMID: 32819363Free PMC Article
Lega IC, Lipscombe LL
Endocr Rev 2020 Feb 1;41(1) doi: 10.1210/endrev/bnz014. PMID: 31722374
Giovannucci E
Gastroenterol Clin North Am 2002 Dec;31(4):925-43. doi: 10.1016/s0889-8553(02)00057-2. PMID: 12489270

Diagnosis

Yang J, Chen C
J Endocrinol 2024 Apr 1;261(1) Epub 2024 Feb 15 doi: 10.1530/JOE-23-0342. PMID: 38285626
Acevedo-Fernández M, Porchia LM, Elguezabal-Rodelo RG, López-Bayghen E, Gonzalez-Mejia ME
Nutr Metab Cardiovasc Dis 2023 Sep;33(9):1725-1732. Epub 2023 May 24 doi: 10.1016/j.numecd.2023.05.023. PMID: 37407310
Janssen JAMJL
Int J Mol Sci 2021 Jul 21;22(15) doi: 10.3390/ijms22157797. PMID: 34360563Free PMC Article
Otto-Buczkowska E, Grzyb K, Jainta N
Pediatr Endocrinol Diabetes Metab 2018;24(1):40-44. doi: 10.18544/PEDM-24.01.0101. PMID: 30083660
Fruzzetti F, Perini D, Russo M, Bucci F, Gadducci A
Gynecol Endocrinol 2017 Jan;33(1):39-42. Epub 2016 Nov 3 doi: 10.1080/09513590.2016.1236078. PMID: 27808588

Therapy

Shah UA, Iyengar NM
JAMA Oncol 2022 Aug 1;8(8):1201-1208. doi: 10.1001/jamaoncol.2022.1769. PMID: 35797039Free PMC Article
Kolb H, Kempf K, Röhling M, Martin S
BMC Med 2020 Aug 21;18(1):224. doi: 10.1186/s12916-020-01688-6. PMID: 32819363Free PMC Article
Rachdaoui N
Int J Mol Sci 2020 Mar 5;21(5) doi: 10.3390/ijms21051770. PMID: 32150819Free PMC Article
Lega IC, Lipscombe LL
Endocr Rev 2020 Feb 1;41(1) doi: 10.1210/endrev/bnz014. PMID: 31722374
Giovannucci E
Gastroenterol Clin North Am 2002 Dec;31(4):925-43. doi: 10.1016/s0889-8553(02)00057-2. PMID: 12489270

Prognosis

Nakatsuka T, Tateishi R
Clin Mol Hepatol 2023 Jan;29(1):51-64. Epub 2022 Jul 29 doi: 10.3350/cmh.2022.0095. PMID: 35903020Free PMC Article
Kasper P, Martin A, Lang S, Kütting F, Goeser T, Demir M, Steffen HM
Clin Res Cardiol 2021 Jul;110(7):921-937. Epub 2020 Jul 21 doi: 10.1007/s00392-020-01709-7. PMID: 32696080Free PMC Article
Vigneri R, Sciacca L, Vigneri P
Trends Endocrinol Metab 2020 Aug;31(8):551-560. Epub 2020 Jun 26 doi: 10.1016/j.tem.2020.05.004. PMID: 32600959
Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, Wapner RJ, Varner MW, Rouse DJ, Thorp JM Jr, Sciscione A, Catalano P, Harper M, Saade G, Lain KY, Sorokin Y, Peaceman AM, Tolosa JE, Anderson GB; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
N Engl J Med 2009 Oct 1;361(14):1339-48. doi: 10.1056/NEJMoa0902430. PMID: 19797280Free PMC Article
Boyd DB
Integr Cancer Ther 2003 Dec;2(4):315-29. doi: 10.1177/1534735403259152. PMID: 14713323

Clinical prediction guides

Love KM, Liu Z
J Clin Endocrinol Metab 2021 May 13;106(6):1553-1565. doi: 10.1210/clinem/dgab078. PMID: 33570554Free PMC Article
Kolb H, Kempf K, Röhling M, Martin S
BMC Med 2020 Aug 21;18(1):224. doi: 10.1186/s12916-020-01688-6. PMID: 32819363Free PMC Article
da Silva AA, do Carmo JM, Li X, Wang Z, Mouton AJ, Hall JE
Can J Cardiol 2020 May;36(5):671-682. Epub 2020 Feb 12 doi: 10.1016/j.cjca.2020.02.066. PMID: 32389340Free PMC Article
Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M
J Transl Med 2020 Feb 27;18(1):104. doi: 10.1186/s12967-020-02277-0. PMID: 32103756Free PMC Article
Hirano T
J Atheroscler Thromb 2018 Sep 1;25(9):771-782. Epub 2018 Jul 12 doi: 10.5551/jat.RV17023. PMID: 29998913Free PMC Article

Recent systematic reviews

Melin J, Forslund M, Alesi S, Piltonen T, Romualdi D, Spritzer PM, Tay CT, Pena A, Witchel SF, Mousa A, Teede H
J Clin Endocrinol Metab 2024 Jan 18;109(2):e817-e836. doi: 10.1210/clinem/dgad465. PMID: 37554096Free PMC Article
Wiebe N, Lloyd A, Crumley ET, Tonelli M
Obes Rev 2023 Oct;24(10):e13588. Epub 2023 Jun 13 doi: 10.1111/obr.13588. PMID: 37309266
Besci Ö, Fırat SN, Özen S, Çetinkaya S, Akın L, Kör Y, Pekkolay Z, Özalkak Ş, Özsu E, Erdeve ŞS, Poyrazoğlu Ş, Berberoğlu M, Aydın M, Omma T, Akıncı B, Demir K, Oral EA
J Clin Endocrinol Metab 2023 Aug 18;108(9):2371-2388. doi: 10.1210/clinem/dgad099. PMID: 36825860
Hernandez AV, Pasupuleti V, Benites-Zapata VA, Thota P, Deshpande A, Perez-Lopez FR
Eur J Cancer 2015 Dec;51(18):2747-58. Epub 2015 Nov 18 doi: 10.1016/j.ejca.2015.08.031. PMID: 26597445
Rendina D, De Filippo G, D'Elia L, Strazzullo P
J Nephrol 2014 Aug;27(4):371-6. Epub 2014 Apr 3 doi: 10.1007/s40620-014-0085-9. PMID: 24696310

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