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MODY

Shepperd(2004)ClinMed;4(2)

Hepatocyte nuclear factor 1alpha (HNS-1α)
Maturity onset diabetes of the young (MODY)
frequently misdiagnosed as T1DM
genetic testing
Sulphonylurea sensitivity
20k people affected in UK
often misdiagnosed as T1DM (young slim adults, marked hyperglycaemia, not appreciated FHx)
Mutations: 65% HNF-1α (MODY3); particularly sensitive to SU
can often be safely transferred to SU without deterioration in glyc control

MODY Types

HNF-1α (MODY 3)

  • 65% prevalence
  • 12q, beta-cell dysfx
  • >90% DM at 40y
  • onset in adol/early adulth
  • progr hyperglyc, may be severe
  • freq microvasc compl
  • usu: lo renal threshold; sensitive to SU

GK (MODY 2)

  • 15% prevalence 
  • 7p; abnml glu sensing, beta-cell dysfx
  • 45% DM at 40y (95% IFG)
  • onset early childh/birth
  • mild hyperglyc, minor deterioration with age
  • usu: reduced birth weight

HNF-4α (MODY 1)

  • 5% prevalence
  • 20q, beta-cell dysfx
  • >80% DM at 40y
  • onset in adol/early adulth
  • progr hyperglyc, may be severe
  • freq microvasc compl
  • usu: lo TG

HNF-1β (MODY 5)

  • 1% prevalence
  • 17q, beta-cell dysfx
  • ?>80% DM at 40y
  • onset in adol/early adulth
  • progr hyperglyc, may be severe
  • retinopathy
  • usu: predom renal phenotype, cysts, renal failure

Others

  • IPF-1(MODY 4): <1%
  • NEUROD1 (MODY6): 0%

Fajans(2001)NEJM:345(13)

  • http://www.ncbi.nlm.nih.gov/pubmed/11575290;  +docs
  • Intro: estimated 1-5% of DM in industrialized countries
  • MODY: heterogenous group, onset usu <25y freq'ly in childhood/adolesc
    • Glucokinase=glycolytic enzyme (MODY 2); GK: ATP+Glu->ADP+Glu-6P; GK acts as glucose sensor in beta cells by controlling rate of glucose entry into glycolytic pathway; partial deficiency leads to MODY2, homozygous leads to neonatal DM;
    • transcription factors
      • hepatocyte nuclear factor (HNF): also in islet cells, kidneys, genitals; in beta cells: regulate expression of insulin gene and genes for proteins for glucose transport, metabolism and mitochondrial metabolism; in liver: regulate lipoprotein biosynthesis
        • HNF-1α (MODY3)
        • HNF-1β (MODY5)
        • HNF-4α (MODY1)=orphan nuclear receptor: regulates expression of HNF-1α
      • insulin promotor factor 1 (IPF-1) (MODY4): regulates transcription of insulin and somatostatin genes
      • neurogenic differentiation factor 1 (NeuroD1)=beta-cell E-box transactivator 2 (BETA2) (MODY6): activates transcription of insulin gene
  • MODY model: Glu transported into beta cell by glucose-transporter protein (GLUT-2); Glucokinase (a/w MODY2) catalyzes transfer of phosphate from ATP to glucose to form glucose-6-phosphate. By means of this reaction, GK functions as the glucose sensor of the cell. Generation of ATP by glucolysis and Krebs cycle leads to inhibition and closure of ATP-sensitive K channels (=target of SU drugs), depolarization of plasma membrane, opening of voltage-dependent Ca channels, influx of extracellular Ca and mobilization of Ca from intracellular stores, leading to fusion of insulin-containing secretory granules with plasma membrane and release of insulin into circulation; MODY-associated transcription factors regulate the transcription of insulin gene (directly:.../indirectly:HNF-4α) and genes encoding enzymes involved in transport and metabolism of glucose;
  • genes expressed in beta cells, mutation cause beta-cell dysfx and DM; genes also expressed in liver and kidney
  • factors that affect insulin sensitivity (infection, puberty, pregnancy, and rarely obesity) may trigger onset of DM
  • Clin Presentation: usu mild asymptomatic hyperglycaemia in nonobese children/adolescents/young adults with a prominent FHx of DM (eg 3+ generations, absence of obesity, young age at presentation; AD pattern)
  • Distinguishing clinical characteristics of MODY and T2DM:
    • inheritance: monogenic AD vs polygenic (gene-gene and gene-environment interactions)
    • age at onset: childh/adolesc/young adulth (usu<25y) vs adulth (usu 40-60), occas adolesc (if obese)
    • pedigree: usu multigenerational vs rarely multigenerational
    • penetrance: 80-95% vs variable (possibly 10-40%)
    • body habitus: non-obese vs usu obese
    • metabolic syndr (DM, IR, Htn, HTG): absent vs usu present
  • MODY1
    • HNF-4α: abnml regulation of gene transcription in beta cells, leading to a defect in metabolic signaling of insulin secretion, beta cell mass, or both;
    • DM; usu microvasc compl, dcrd TG, A1, C3, Lp(a)
    • Rx: usu OHA, insulin (30-40%);
  • MODY2
    • Glucokinase: defect in sensitivity of beta cells to glucose due to dcrd glucose phosphorylation; defect in hepatic storage of glucose as glycogen;
    • IFG, IGT, DM, normal proinsulin/insulin ratio (cf icrd in MODY3)
    • Rx: diet and exercise
    • if homozygous: neonatal DM, requiring insulin
  • MODY3
    • HNF-1α: abnml regulation of gene transcription in beta cells, leading to a defect in metabolic signaling of insulin secretion, beta-cell mass, or both
    • DM, usu microvasc compl, renal glycosuria, icrd sens to SU drugs, icrd proinsulin/insulin ratio (cf nml in MODY2)
    • Rx: usu OHA, insulin (30-40%);
  • MODY4
    • IPF-1: abnml transcriptional regulation of beta cell development and fx
    • DM;
    • Rx: OHA, insulin
    • if homozygous: pancreatic agenesis, neonatal DM requiring insulin
  • MODY5
    • HNF-1β: abnml regulation of gene transcription in beta cells, leading to a defect in metabolic signaling of insulin secretion, beta cell mass, or both
    • DM, renal cysts and other abnmlties of renal development; progressive nondiabetic renal dysfx, leading to CRF; internal genital abnmlties in females
    • Rx: insulin
  • MODY6
    • NeuroD1 or BETA2: abnml transcriptional regulation of beta cell development and fx
    • DM
    • Rx: insulin
 
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