title: Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
abstract: OBJECTIVE
  Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes.
  
  
  OBJECTIVE
  To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations.
  
  
  METHODS
  Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years).
  
  
  METHODS
  Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease.
  
  
  RESULTS
  Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% CI, 0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%], P<.001). Thirty percent of patients with GCK had retinopathy (95% CI, 21%-41%) compared with 14% of controls (95% CI, 7%-23%, P=.007) and 63% of patients with YT2D (95% CI, 51%-73%, P<.001). Neither patients with GCK nor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% CI, 0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%) of YT2D patients had proteinuria (P<.001 vs GCK) and 21% (95% CI, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with GCK (2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present in 29% (95% CI, 20%-50%) of YT2D patients (P<.001). Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001).
  
  
  CONCLUSIONS
  Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia.
authors.affiliation: National Institue for Health Research, Exeter Clinical Research Facility, Exeter Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Steele
authors.affiliation: National Institue for Health Research, Exeter Clinical Research Facility, Exeter Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Beverley M
authors.initials: BM
authors.lastname: Shields
authors.affiliation: National Institue for Health Research, Exeter Clinical Research Facility, Exeter Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Kirsty J
authors.initials: KJ
authors.lastname: Wensley
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Colclough
authors.affiliation: National Institue for Health Research, Exeter Clinical Research Facility, Exeter Medical School, University of Exeter, Exeter, United Kingdom2Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, United.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: National Institue for Health Research, Exeter Clinical Research Facility, Exeter Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D048909:Diabetes Complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D005941:Glucokinase; D006442:Glycated Hemoglobin