gck - mody ( gck diabetes , glucokinase diabetes , or mody2 ) is a monogenic condition caused by heterozygous mutations in the gene encoding glucokinase ( gck ) .
it is characterized by chronic , lifelong , and mild hyperglycemia present from birth , and less than 50% of patients fulfil the criteria for overt diabetes .
the increased risk of atherosclerotic vascular disease  as compared with healthy individuals without diabetes  is known in subjects with impaired glucose tolerance , patients with type 2 diabetes , and patients with metabolic syndrome [ 3 , 4 ] .
noninvasive imaging techniques , such as carotid intima - media thickness ( cimt ) measurements , may help to stratify this risk of atherosclerosis , as well as the risk of myocardial ischemia : the cimt has been shown to independently predict coronary events in type 2 diabetes and cardiovascular diseases .
however , the situation in gck - mody is likely to be different from that in type 2 diabetes : patients with gck - mody have increased fasting blood glucose and relatively low 2-hour post - ogtt blood glucose without other components of metabolic syndrome or insulin resistance .
such a blood glucose profile has been shown to be associated with lower rates of cardiovascular mortality among patients with type 2 diabetes .
importantly , niskanen et al .   demonstrated that components of insulin resistance syndrome , including hyperinsulinemia after an oral glucose load , serum lipid abnormalities , and elevated blood pressure , are major determinants of cimt in patients with diabetes .  
the risk of macrovascular complications in gck - mody is considered low , but the data are scarce .
we aimed to evaluate the carotid intima - media thickness ( cimt ) as an indicator of this risk in gck - mody patients aging 35 years or older and their unaffected relatives , who share a similar environment and lifestyle .
we studied 27 patients from 20 czech families with genetically confirmed gck - mody ( age 3575 years ; median 46 years ) and 24 unaffected family members ( siblings , parents , and partners ) representing the control group ( age 3579 years ; median 50 years ) .
each of the 20 participating families contributed 1 to 3 patients with gck - mody and 1 to 3 control individuals matched by age and gender .
control individuals with fasting blood glucose more than 5.6  mmol / l ( 100  mg / dl ) and/or with a known history of diabetes were excluded from the study .
the identification of families with gck - mody has been reported previously [ 9 , 10 ] .
the study protocol was approved by the ethics committee of the 3rd faculty of medicine , charles university in prague , czech republic .  
the structured assessment included a questionnaire , anthropometric examination and blood sampling for biochemical analysis .
high - resolution b - mode carotid ultrasonography ( using phillips iu22 ultrasound ) was performed to measure the cimt of the distant wall for 1  cm lengths of the carotid bifurcation and the internal carotid and right and left common carotid arteries .
the mean cimt values of 10 sites were combined in an unweighted average to produce an overall cimt .
the upper normal limit of cimt was set to 0.7  mm [ 12 , 13 ] .
the patient history of coronary heart disease and ischemic stroke was obtained from medical records .
the clinical and demographic characteristics of gck mutation carriers and control individuals were compared using welch 's two - sample t - tests ( continuous variables ) and fisher 's exact tests ( categorical variables ) .
mixed linear regression models with cimt , blood pressure , and serum creatinine as outcomes were used to estimate and test the adjusted effects of gck mutation status . age , gender , and mutation status
no significant differences in baseline characteristics were found between patients and control individuals , with the exception of fasting blood glucose ( gck - mody 7.6  mmol / l , sd  1.2 ( 136.4  mg / dl ) ; controls 5.3  mmol / l , sd  0.3 ( 95.4  mg / dl ) ; p < 0.0001 ) and glycated hemoglobin hba1c ( gck - mody 6.9% ( sd  1.0 ) , 52  mmol / mol ( sd  10 ) ; controls 5.7% ( sd  0.4 ) , 39  mmol / mol ( sd  3 ) ; p < 0.0001 ) ( table 1 ) .
the prevalence of smokers and hypertensive patients was similar in both samples ( p = 1 ) .
the measured cimt values for participants with and without gck mutations are shown in figure 1 .
the mean cimt was 0.707  mm ( range : 0.41.1 ) in gck - mody patients and was 0.692  mm ( range : 0.41.1 ) in healthy control individuals . according to the published recommendations [ 12 , 13 ]
after adjusting for age , gender , and family status , the estimated mean difference in cimt between patients and healthy individuals increased slightly to 0.049  mm ( 95% ci from 0.026 to 0.123 ; p = 0.19 ) . as expected , the estimated trends of mean cimt indicated a moderate increase in cimt with age and mutation status ( see regression lines plotted in figure 1 ) .
carotid plaques ( local intima - media thickening exceeding 1  mm and protruding into the lumen ) were identified in 7 ( 25.9% ) patients and 3 ( 12.5% ) control individuals ( p = 0.1 ) , but all of these plaques were hemodynamically insignificant .  
myocardial changes typical of ischemic heart disease described on echocardiography and/or ecg were detected in three of 27 patients with gck - mody and two of the 24 healthy control individuals ( p = 0.866 ) .
three study participants had suffered from myocardial infarction ( two with gck - mody and one control individual ) ( p = 0.895 ) in the past , and two had suffered from ischemic stroke ( one with gck - mody and one control individual ) .
a similar proportion of participants ( 35% ) from both groups were treated for hypertension with one or more antihypertensive drugs .
four of the 27 patients with gck - mody ( 14.8% ) were treated with oral hypoglycemic agents , and one was treated with insulin .
to the best of our knowledge , the present study is the first case - control study including the cimt measurements of gck - mody patients older than 35 years .
the results are consistent with the mild natural course of gck - mody and confirm that gck mutation is not associated with an increased risk of developing macroangiopathic complications .
the 95% confidence interval of the cimt difference , adjusted for age , family , and gender , is 0.026 to + 0.123  mm , indicating that the possible increase in cimt associated with gck mutation is low and most likely clinically insignificant .
the absence of serious chronic microvascular complications in gck - mody was observed by page et al .   and
velho et al . [ 16 , 17 ] , who described proliferative retinopathy in less than 4% , proteinuria in 6% , and peripheral neuropathy in 5% of patients with hyperglycemia at more than 5 years after diagnosis .
a major problem with assessing diabetic complications in those patients is the differentiation between patients who only have gck - mody and those who develop type 2 diabetes in addition to gck - mody .
it is generally assumed that patients with gck - mody do not necessarily develop insulin resistance or dyslipidemia in the natural disease course , and their glucose tolerance remains stable over many years . nevertheless , carrying
a gck mutation does not protect against the development of type 2 diabetes , which occurs at a similar prevalence in gck - mody patients and in the general population .  
it has been reported that metabolic syndrome and insulin resistance are the major components of atherosclerosis risk in patients with diabetes and also in individuals without diabetes with insulin resistance [ 3 , 20 , 21 ] , whereas the role of hyperglycemia in cardiovascular disease associated with type 2 diabetes is less clear .
in contrast with patients with type 2 diabetes , patients with gck - mody have mild hyperglycemia without other components of metabolic syndrome or insulin resistance . therefore , our study adds to the accumulating evidence that chronic mild hyperglycemia without additional components of metabolic syndrome has a milder effect on the development of macrovascular complications compared with the same glycemic levels associated with metabolic syndrome components .
admittedly , more subtle effects on cimt would remain undetected , as the present study is moderately sized .
the numbers of available patients in other studies are , however , comparable  a detailed analysis of the effects of p.gly299arg mutation in the gck gene was limited to a single large pedigree , whereas another study reporting selected metabolic parameters and history data included 35 families , but these subjects were not examined at a single centre , and the data did not include cimt [ 16 , 17 ] .
thus , the number of participants may reflect a compromise between the depth of the acquired data and the subjects ' willingness to undergo a complicated set of investigations .  
patients with gck - mody exhibit only a small increase in glucose levels after oral glucose loading .
by contrast , patients with type 2 diabetes have relatively high 2-hour glucose levels ( as a proxy for postprandial glucose levels ) , indicating that postprandial glucose levels could be the most pathogenic glycemic factor for developing micro- and macrovascular complications .
the cimt has been shown to correlate more strongly with postprandial glycemia than with fasting hyperglycemia .
additionally , the serum hs - crp levels are lower in gck - mody patients than in patients with type 2 diabetes .
however , a common variant in the pancreatic gck promoter has been shown to influence the risk of diabetes complications .
showed   that the a allele at c.30g > a of gck was associated with an increased risk of coronary artery disease in not only patients with type 2 diabetes but also individuals who did not have diabetes , albeit with a much weaker association ( or = 1.27 ; 95% ci 1.021.59 ) . additionally , the snp rs4607517 , which is in linkage disequilibrium with c.30g > a , has been associated with fasting glucose in genome - wide association studies .
the association between components of the fasting glucose genetic risk score ( represented by five snps , including rs4607517 ) and cimt has been described with an increment of 0.0048  mm in carriers .   in conclusion ,
our data indicate that the natural course of mild lifelong hyperglycemia is associated with a low risk of developing diabetic macrovascular complications .
however , patients with gck - mody should take steps to reduce the risk of developing  classical  type 2 diabetes in addition to gck - mody that is , avoid obesity and maintain a high level of physical activity .
our data support a conservative therapeutic approach for hyperglycemia in nonpregnant patients with gck - mody .
other risk factors for micro- and macrovascular complications should be treated according to present guidelines .
 
 aim . 
 gck - mody is an autosomal dominant form of diabetes caused by heterozygous mutations in the glucokinase gene leading to a lifelong mild hyperglycemia . 
 the risk of macrovascular complications is considered low , but studies are limited . 
 we , therefore , investigated the carotid intima - media thickness ( cimt ) as an indicator of macrovascular complications in a group of patients with gck - mody . 
 methods . twenty - seven gck mutation carriers and 24 controls recruited among their first - degree relatives 
 were compared , all aging over 35 years . 
 the cimt was tested using a high - resolution b - mode carotid ultrasonography . 
 medical history , anthropometry , and biochemical blood workup were obtained . 
 results . 
 the mean cimt was 0.707  0.215  mm ( mean  sd ) in gck mutation carriers and 0.690  0.180  mm in control individuals . 
 when adjusted for age , gender , and family status , the estimated mean difference in cimt between the two groups increased to 0.049  mm ( p = 0.19 ) . 
 no difference was detected for other characteristics , with the exception of fasting blood glucose ( gck - mody 7.6  mmol / l  1.2 ( 136.4  mg / dl ) ; controls 5.3  mmol / l  0.3 ( 95.4  mg / dl ) ; p < 0.0001 ) and glycated hemoglobin hba1c ( gck - mody 6.9%  1.0% , 52  mmol / mol  10 ; controls 5.7%  0.4% , 39  mmol / mol  3 ; p 
 < 0.0001 ) . 
 the frequency of myocardial infarction and ischemic stroke did not differ between groups . 
 conclusion . 
 our data indicate that the persistent hyperglycemia in gck - mody is associated with a low risk of developing diabetic macrovascular complications . 