People with this mis-sense mutation in the gene that encodes glucokinase (GCK), part of the pancreatic beta cell glucose sensor, basically have their sugar thermostat, their glucostat, set too high. They don't produce insulin in response to blood glucose in the pre-diabetic range. In this study, average HbA1c is 6.9%. But the incidence of insulin resistance, obesity, dyslipdaemia, and hypertension in this population is the same as in the normal controls, who have average HbA1c of 5.8% here.
So basically we are looking at mild hyperglycaemia without hyperinsulinaemia and its sequelae.
I think this is a good model for people with type 2 diabetes who have reversed the disease to a pre-diabetic level on a low carb diet, lost weight, and corrected hypertension. No carbs = low insulin, so how much of a problem is mild hyperglycaemia if it persists?
Also, do some people diagnosed with T2DM or prediabetes who go low carb have the GCK mutation without knowing it, meaning they will not get normal blood sugars?
JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980.
Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT.
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.
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.
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.
BAM! as they say. Without high insulin, glucose at this level doesn't damage the blood vessels any more than "normal" BG does in a population with "normal" insulin responses to carbohydrate.
It does damage the eyes (but not the nerves), probably because the polyol pathway is insulin-independent, but the rate of retinopathy is already high, at 14%, in the "normal" population. Neuropathy has both a glycotoxic and a microvascular pathology, so is more dependent on hyperinsulinaemia than retinopathy.
A feature of GCK mutation is that blood glucose is highest in the most overweight individuals; this seems to show increased FFA flux boosting gluconeogenesis, or some extra effect of NAFLD increasing insulin resistance.
This is from a paper comparing a sample with the GCK mutation with their normal, non-diabetic family members.
"In subjects with the mutation, beta cell function was impaired, being geometric mean 63 % (normal-100 %) compared with 126 % in the subjects without the mutation (p less than 0.001) measured by HOMA and in a subset assessed by CIGMA 59 % and 127 % (p less than 0.01 ), respectively. There was no difference in fasting insulin concentrations, insulin sensitivity, lipid concentrations or blood pressure between the groups. The haemoglobin A was raised (mean 6.5 % compared with 5.5 % in the subjects without the mutation), but microvascular and macrovascular complications were uncommon."
The authors of the first paper think this is a model for glycaemic control that attains recommended HbA1c targets for T1D and T2D. I don't think this can be the case if extra insulin or sulfonylureas are being used to meet these targets because the diet is still high in carbs. It is a model for the early stages of dietary control of diabetes, with reduced insulin levels or requirements and HbA1c trending down, and weight and blood pressure normalising.
The mechanisms that cause vascular disease in diabetes, including smooth muscle cell dysfunction and impaired eNOS signalling, are the same ones that are supposed to initiate atherosclerosis, whatever the role of lipoproteins in its development. Say it again - it's the insulin stupid.
 Diabet Med. 1995 Mar;12(3):209-17.
Clinical characteristics of subjects with a missense mutation in glucokinase.
Page RC1, Hattersley AT, Levy JC, Barrow B, Patel P, Lo D, Wainscoat JS, Permutt MA, Bell GI, Turner RC.