Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.

OBJECTIVE: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic ß-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. METHODS: Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. RESULTS: GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated ß-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in ß-cells. For epinephrine, we found increased responses in GCK-MODY patients, in ß-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. CONCLUSIONS: Our data suggest that glucokinase in brain and other non ß-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.

Prolonged unilateral disuse osteopenia 14 years post external fixator removal: a case history and critical review.

Disuse osteopenia is a complication of immobilisation, with reversal generally noted upon remobilisation. This case report focuses on a patient who was seen 18 years following a road traffic collision when multiple fractures were sustained. The patient had an external fixator fitted for a tibia and fibula fracture, which remained in situ for a period of 4 years. Following removal, the patient was mobilised but, still required a single crutch to aid walking. Fourteen years post removal of the fixator, the patient had a DXA scan which, demonstrated a T-score 2.5 SD lower on the affected hip. This places the patient at an increased risk of hip fracture on this side, which requires monitoring. There appear to be no current studies investigating prolonged disuse-osteopenia in patients following removal of long-term external fixators. Further research is required to quantify unilateral long-term effects to bone health and fracture risk in this population.

Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73.

The UK Prospective Diabetes Study (UKPDS) showed that a more intensive glucose control policy reduced risk of diabetic complications. As hypoglycemia is a barrier to achieving glycemic targets, we examined its occurrence and contributing factors in UKPDS patients randomized to and remaining for 6 years on diet, sulfonylurea, metformin (overweight subjects only), or insulin monotherapy from diagnosis of Type 2 diabetes. Self-reported hypoglycemic episodes were categorized as (1) transient, (2) temporarily incapacitated, (3) requiring third-party assistance, and (4) requiring medical attention, recording the most severe episode each quarter. Proportions of patients reporting at least one episode per year were calculated in relation to therapy, HbA(1c), and clinical characteristics. In 5063 patients aged 25-65 years, only 2.5% per year reported substantive hypoglycemia (Grades 2-4) and 0.55% major hypoglycemia (Grade 3 or 4). Hypoglycemia was more frequent in younger (4.0% <45 years vs. 2.2% >or=45 years), female (3.0% vs. 2.2% male), normal weight (3.6% body mass index <25 kg/m(2) vs. 1.9% >or=25 kg/m(2)), less hyperglycemic (5.2% HbA(1c) <7% vs. 2.3% >or=7%), or islet autoantibody-positive patients (4.3% vs. 2.1% negative) (all P<.0001). More on basal insulin reported hypoglycemia (3.8% per year) than diet (0.1%), sulfonylurea (1.2%), or metformin (0.3%) therapy, but less than on basal and prandial insulin (5.3%) (all P<.0001). Low hypoglycemia rates seen during the first 6 years of intensive glucose lowering therapy in Type 2 diabetes are unlikely to have a major impact on attempts to achieve guideline glycemic targets when sulfonylurea, metformin, or insulin are used as monotherapy.

The impact of the angiotensin-converting enzyme insertion/deletion polymorphism on severe hypoglycemia in Type 2 diabetes.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene (ACE) is associated with altered serum ACE activity. Raised ACE levels and the ACE DD genotype are associated with a 3.2 to 6.8-fold increased risk of severe hypoglycemia in type 1 diabetes. This relationship has not been assessed in type 2 diabetes. We aimed to test for association of the ACE I/D polymorphism with severe hypoglycemia in type 2 diabetes. Patients with type 2 diabetes (n = 308), treated with insulin (n = 124) or sulphonylureas (n = 184), were classified according to whether or not they had previously experienced severe hypoglycemia. Samples of DNA were genotyped for the ACE I/D polymorphism using two alternative polymerase chain reactions to prevent mistyping due to preferential amplification of the D allele. Overall, 12% of patients had previously experienced one or more episodes of severe hypoglycemia. This proportion did not differ between genotype groups (odds ratio (95% confidence limits) for carriers of D allele relative to II homozygotes: 0.79 (0.35-1.78)). This study found no evidence for association of the ACE I/D polymorphism with severe hypoglycemia frequency in patients with type 2 diabetes. However, we cannot rule out a smaller effect (odds ratio

Prediction of visceral adipose tissue using air displacement plethysmography in children.

OBJECTIVE: To determine the ability of air displacement plethysmography (ADP) to predict visceral adipose tissue (VAT) volume in children. RESEARCH METHODS AND PROCEDURES: Fifty-five (33 boys/22 girls) white children 13 to 14 years old were studied. Anthropometric measures were collected for body mass, stature, BMI, and waist-to-hip ratio (WHR), and body fat percentage was estimated from triceps and subscapular skinfolds, bioelectrical impedance analysis, and ADP. VAT volume was determined using magnetic resonance imaging, using a multiple slice protocol at levels L1 to L5. RESULTS: Boys had significantly (p < or = 0.05) less VAT volume than girls [645.1 (360.5) cm(3) vs. 1035.8 (717.3) cm(3)]. ADP explained the greatest proportion of the variance in VAT volume compared with the other anthropometric measures. Multiple regression analysis indicated that VAT volume was best predicted by ADP body fat percentage in boys [r(2) = 0.81, SE of the estimate (SEE) = 160.1, SEE coefficient of variation = 25%] and by WHR and BMI in girls (r(2) = 0.80, SEE = 337.71, SEE coefficient of variation = 33%). DISCUSSION: Compared with the other anthropometric measures, ADP explains the greatest proportion of the variance in VAT volume in children 13 to 14 years old. For boys, ADP is the tool of choice to predict VAT volume, yet using the more simply collected measures of BMI and WHR is recommended for girls. However, large SE of the estimates remained, suggesting that if precision is needed, there is no surrogate for direct imaging of VAT.

Capillary pressure in subjects with type 2 diabetes and hypertension and the effect of antihypertensive therapy.

Raised capillary pressure has been implicated in the formation of diabetic microangiopathy in type I diabetes, in which it is elevated in those with the earliest signs of diabetic kidney disease but remains normal in those without complications. In subjects with type 2 diabetes without complications, capillary pressure is normal, although alterations in the pressure waveforms suggested enhanced wave reflections. The nature of skin capillary pressure in subjects with type 2 diabetes and hypertension remains to be elucidated, as does the effect of blood pressure-lowering therapy on capillary pressure in these subjects. Three studies were performed in well-matched groups. First, capillary pressure was elevated in hypertensive subjects with type 2 diabetes compared with normotensive subjects with type 2 diabetes (20.2 [17.4 to 22.7] mm Hg versus 17.7 [16.1 to 18.9] mm Hg, respectively, P<0.03, Mann-Whitney U test). Second, no significant difference was detected between hypertensive subjects with type 2 diabetes and hypertensive subjects without type 2 diabetes (19.4 [15.8 to 21.3] mm Hg versus 17.2 [15.1 to 19.8] mm Hg, respectively, P=0.5, Mann-Whitney U test). Finally, patients with type 2 diabetes were recruited to a case-control study. Seven subjects received blood pressure-lowering therapy and 8 did not. Therapy reduced capillary pressure from 18.2 [15.8 to 20.1] mm Hg to 15.9 [15.4 to 17.0] mm Hg (P=0.024 ANOVA), in contrast to the lack of effect of time alone. Mean arterial pressure was reduced from 110 [102 to 115] mm Hg to 105 [101 to 111] mm Hg (P=0.006, ANOVA). These findings provide a plausible mechanism by which reducing arterial hypertension may reduce the risk of microangiopathy in type 2 diabetes.