Prevalence of Vascular Complications Among Patients With Glucokinase Mutations and Prolonged, Mild Hyperglycemia
- Autores: Anna M Steele, Beverley M. Shields, Kirsty J Wensley, Kevin Colcough, Sian Ellard, A. T. Hattersley
- Localización: JAMA: the journal of the American Medical Association, ISSN 0098-7484, Vol. 311, Nº. 3, 2014, págs. 279-286
- Idioma: inglés
- Enlaces
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Resumen
Importance 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.
Design, Setting, and Participants 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).
Main Outcomes and Measures 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 and Relevance 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.
In both type 11 and type 2 diabetes,2 hyperglycemia is associated with microvascular complications over time. Intensive treatment to lower blood glucose levels reduces the development of microvascular complications.3,4 In type 1 diabetes, lowering the blood glucose has been shown to have long-term beneficial effects on reducing macrovascular disease.5 In type 2 diabetes, the follow-up of the United Kingdom Prospective Diabetes Study (UKPDS) showed that lowering the level of hyperglycemia reduces the risk of macrovascular end points.6 Additionally, associations have been seen between measures of glycemia and coronary heart disease throughout the nondiabetic range.7 Except for during pregnancy, a target glycated hemoglobin (HbA1c) level lower than 7% has been recommended for people with diabetes,8,9 yet longitudinal studies have few patients with sustained glycemia within this recommended target.1,2 It is therefore of clinical importance to know the complication prevalence and severity in individuals with a long and sustained duration of glycemia at a level above that of the nondiabetic population but that mimics the current target range of 7%. Individuals with a heterozygous, inactivating mutation in the gene encoding the enzyme glucokinase have mild hyperglycemia that is present from birth. Their HbA1c level is typically between 5.6% and 7.6%,10,11 and their fasting plasma glucose level is between 99 mg/dL and 156 mg/dL (to convert to millimoles per liter, multiply by 0.0555).11,12 These patients rarely require pharmacological treatment,13 and their lipid and blood pressure levels are similar to that of the general population.14,15 The hyperglycemia in patients with a glucokinase GCK mutation is therefore an isolated risk factor for complications.14,15 We assessed the prevalence and severity of microvascular and macrovascular complications in patients with GCK mutations to give further information about the relationship between current glycemic targets and diabetes-related complications. We also assessed these outcomes in nondiabetic, nonmutation carriers (control) and in patients with young-onset type 2 diabetes (YT2D).
