Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation.

AIM: To assess determinants of fetal growth in the offspring of pregnant women with hyperglycaemia due to a heterozygous glucokinase (GCK) gene mutation. METHODS: Details of gestational age at delivery, fetal birth weight and maternal antenatal treatment were collected from patients and retrospective case note review of 82 offspring born to 42 women with GCK gene mutations and 31 offspring born to 13 unaffected normoglycaemic women with an affected partner. Fetal genotype was determined using direct sequencing from either a mouth swab or a blood sample. RESULTS: In mothers with GCK mutations, non-mutation-carrying offspring were heavier than mutation-carrying offspring (corrected birth weight 3.9 +/- 0.6 vs. 3.2 +/- 0.8 kg; P < 0.001) and more likely to be macrosomic (> 4.0 kg; 39% vs. 7%, P = 0.001). There was no difference in corrected birth weight between offspring of insulin- and diet-treated women (3.7 +/- 0.7 vs. 3.8 +/- 0.6 kg; P = 0.1), although insulin-treated mothers delivered earlier (37.5 +/- 1.7 vs. 38.9 +/- 2.3 weeks; P < 0.001) due to increased obstetric intervention. CONCLUSIONS: Offspring of women with GCK mutations are at increased risk of macrosomia and its obstetric consequences. Fetal birth weight is predominantly altered by fetal genotype and not treatment of maternal hyperglycaemia with insulin. This probably reflects the large effect of a fetal GCK mutation on fetal insulin secretion and the difficulty in reducing the regulated maternal glycaemia caused by a glucose sensing defect in people with GCK mutations.

Impact of hormone replacement therapy on microvascular function in healthy and Type 2 diabetic postmenopausal women.

AIMS: Hormone replacement therapy (HRT) has been previously reported to modulate vascular function and cardiovascular risk. Its impact on the macrocirculation has previously been explored, however, little data is available on its impact on the microcirculation. This study aimed to determine the impact of HRT on microvascular function in healthy and Type 2 diabetic postmenopausal women (n=20 and 17, respectively). METHODS: Microvascular function was assessed by skin maximum hyperaemia, skin hyperaemic response to iontophoretically applied acetylcholine (endothelial-dependent vasodilator) and sodium nitroprusside (endothelial-independent vasodilator), capillary pressure and the microvascular filtration capacity. Microvascular assessments were carried out at baseline and repeated following 6 months' oral hormone replacement therapy (1 mg oestradiol/0.5 mg norethisterone or 1 mg unopposed oestradiol for hysterectomized women). RESULTS: Following 6 months' therapy there were no significant changes in microvascular assessments in the healthy women. In the diabetic women there was a reduction in the skin hyperaemic response to acetylcholine [median pretreatment peak response: 1.95 (25th, 75th centiles: 1.54, 2.30) V vs. post-treatment peak response: 1.53 (1.30, 1.91) V (P=0.011, Wilcoxon's signed rank test)] and sodium nitroprusside [median peak response 1.59 (1.37, 1.99) vs. 1.35 (0.92, 1.63) V (P=0.011)] with HRT, but no other changes. CONCLUSION: These data suggests that HRT does not affect microvascular function in healthy women, but adversely affects it in diabetic women. These findings may help to explain why HRT fails to provide the predicted cardiovascular protection, and raises the possibility that HRT influences microangiopathy progression in diabetic women.

Preserved insulin response to tolbutamide in hepatocyte nuclear factor-1alpha mutation carriers.

AIMS: Diabetic subjects with mutations in the gene encoding hepatocyte nuclear factor (HNF)-1alpha (MODY3) are prone to develop hypoglycaemia at low doses of glibenclamide, interpreted as sulphonylurea hypersensitivity. The present study was undertaken to compare the plasma insulin responses to glucose and tolbutamide in HNF-1alpha mutation carriers with those of healthy control subjects. METHODS: Seven mutation carriers; three normoglycaemic, two with impaired glucose tolerance, and two with newly detected diabetes, underwent an oral glucose tolerance test and a tolbutamide-modified intravenous glucose tolerance test with measurements of plasma insulin. Twenty-two healthy subjects served as controls. RESULTS: The plasma insulin response to intravenous glucose was reduced in the HNF-1alpha mutation carriers compared to the control subjects, with an area under the curve (median (interquartile range)) of 812 min pmol/l (421, 1647) and 1933 min pmol/l (1521, 2908), respectively (P = 0.03). In striking contrast, the plasma insulin response to tolbutamide was preserved, with an area under the curve of 2109 min pmol/l (1126, 3172) and 2250 min pmol/l (1614, 3276) in the mutation carriers and control subjects, respectively. CONCLUSIONS: HNF-1alpha mutation carriers are characterized by preserved tolbutamide-induced insulin secretion. Compared to healthy subjects, our MODY3 individuals did not show any increased serum insulin response to tolbutamide, suggesting that HNF-1alpha mutation carriers are not characterized by sulphonylurea hypersensitivity.

Influence of maternal and fetal glucokinase mutations in gestational diabetes.

We report 2 insulin-treated pregnancies in a mother with hyperglycemia resulting from a glucokinase gene mutation. The inheritance of a glucokinase mutation in 1 child reduced his intrauterine growth (birth weight less than first percentile) by reducing fetal insulin secretion. We discuss the implications for obstetric management of patients with glucokinase mutations.

Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes.

BACKGROUND: Intensive treatment to achieve good glycaemic control in diabetic patients is limited by a high frequency of hypoglycaemia. The glucose concentrations at which symptoms and release of counter-regulatory hormones takes place have not been studied in patients with well controlled type-2 diabetes. METHODS: We studied seven well controlled, non-insulin treated, type-2 diabetic patients (mean HbA1c [corrected according to Diabetes Control and Complications Trial] 7.4%, SD 1.0) and seven healthy controls matched for age, sex, and body mass index with a stepped hyperinsulinaemic hypoglycaemic glucose clamp. Symptoms, cognitive function, and counter-regulatory hormone concentrations were measured at each glucose plateau, and the glucose value at which there was a significant change from baseline was calculated. FINDINGS: Symptom response took place at higher whole-blood glucose concentrations in diabetic patients than in controls. Counter-regulatory release of epinephrine, norepinephrine, growth hormone, and cortisol showed a similar pattern--eg, at blood glucose concentrations of 3.8 mmol/L [SD 0.4] vs 2.6 [0.3] for epinephrine. INTERPRETATION: Glucose thresholds for counter-regulatory hormone secretion are altered in well controlled type-2 diabetic patients, so that both symptoms and counter-regulatory hormone release can take place at normal glucose values. This effect might protect type-2 diabetic patients against episodes of profound hypoglycaemia and make the achievement of normoglycaemia more challenging in clinical practice.

Audit of cardiac catheterisation in a district general hospital: implications for training.

OBJECTIVE: To assess complications of diagnostic cardiac catheterisation in a non-surgical centre by review of the first three years' experience and audit of 2804 diagnostic left heart procedures. DESIGN: Analysis of a prospective database of cardiac catheter procedures. SETTING: District general hospital without available on site cardiac surgery. RESULTS: The rate of major complications of cardiac catheterisation was 0.07%. Mortality was 0. 07%, and the rate of arterial complications (requiring surgical repair) was 0.24% for brachial arteries and 0.17% for femoral. These results are comparable to those reported from national and international surgical centres. CONCLUSION: A diagnostic cardiac catheterisation service can be offered in non-surgical hospitals without an increased risk to patients. It highlights the relevance of training in angioplasty and questions the appropriateness of starting preliminary invasive cardiology training of specialist registrars in district general hospitals.