OBJECTIVE -Patients with diabetes due to hepatocyte nuclear factor (HNF)-1␣ mutations have ␤-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1␣ mutation carriers. RESEARCH DESIGN AND METHODS-A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing.RESULTS -HNF-1␣ mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked ␤-cell deficiency with reduced insulinogenic index (53.5 [31.5-90.9] vs. 226.0 [126.0 -407.1], SD [range], P Ͻ 0.001) and area under the curve for insulin (P Ͻ 0.001). Insulin sensitivity was increased in mutation carriers (homeostatic model assessment of insulin sensitivity 144.6 [82.7-252.7] vs. 100 [66.9 -149.4], P ϭ 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects (P ϭ 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1-11.8 vs. 6.2-8.4 mmol/l, P ϭ 0.002). The seven subjects with diabetes all showed glycosuria. CONCLUSIONS -We conclude that marked ␤-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1␣ mutation carriers. The presence of glycosuria post-glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test Ͼ8.4 mmol/l. Patients with HNF-1␣ mutations have normal glucose tolerance in early childhood but typically present in their teens or early adult life with symptomatic diabetes and have increasing hyperglycemia and treatment requirements throughout life (6,7). Progressive ␤-cell failure leads to increasing hyperglycemia due to reduced insulin secretion in response to hyperglycemia (6,8 -11). An increased proinsulin-to-insulin ratio was reported to be characteristic of the ␤-cell defect in HNF-1␣ subjects with diabetes in one study (6) but not in a second (9). A feature of the ␤-cell defects is that they are more sensitive to the hypoglycemic effects of sulfonylureas compared with patients with type 2 diabetes (12). There is controversy as to whether diabetic subjects with HNF-1␣ mutations show altered insulin sensitivity. Insulin sensitivity has been reported as increased (6,10), similar (9), and reduced (11). Marked insulin resistance and the associated dyslipidemia are not clinical features of subjects with diabetes due to an HNF-1␣ mutation (13). Diabetes CareA low renal threshold for glucose was first noted in MODY families by Tattersall in 1974 (14). Two of the families originally reported have since been shown to have HNF-1␣ mutations (15; A...

The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obesity. However, although circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from inactive cortisone, by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose tissue in human obesity are debated in the literature, global inhibition of 11betaHSD1 improves insulin sensitivity. We have determined the effects of significant weight loss on cortisol metabolism and adipose tissue 11betaHSD1 expression after 10-wk ingestion of a very low calorie diet in 12 obese patients (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). All patients achieved significant weight loss (14.1 +/- 1.3% of initial body weight). Total fat mass fell from 41.8 +/- 1.9 to 32.0 +/- 1.7 kg (P < 0.0001). In addition, fat-free mass decreased (64.4 +/- 3.4 to 58.9 +/- 2.9 kg; P < 0.0001) and systolic blood pressure and total cholesterol also fell [systolic blood pressure, 135 +/- 5 to 121 +/- 5 mm Hg (P < 0.01); total cholesterol, 5.4 +/- 0.2 to 4.8 +/- 0.2 mmol/liter (P < 0.05)]. The serum cortisol/cortisone ratio increased after weight loss (P < 0.01). 11betaHSD1 mRNA expression in isolated adipocytes increased 3.4-fold (P < 0.05). Decreased 11betaHSD1 activity and expression in obesity may act as a compensatory mechanism to enhance insulin sensitivity through a reduction in tissue-specific cortisol concentrations. Inhibition of 11betaHSD1 may therefore be a novel, therapeutic strategy for insulin sensitization.

Our data provide further evidence that genetic factors are important in determining urinary albumin excretion and renal disease associated with Type 2 diabetes and suggest that genes that affect systemic arterial blood pressure but not those relating to insulin resistance or inflammation are likely to be implicated.

Aims/hypothesis: Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may alter fetal insulin secretion and insulin action. Subjects, materials and methods: To assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term, UK Caucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids. Results: As expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16-0.4, p<0.01 for all) and maternal BMI (r=0.11, p=0.005), maternal glucose (r=0.25, p<0.001) and maternal insulin resistance (r=0.23, p<0.001). Paternal fasting insulin and insulin resistance were correlated with cord insulin (r=0.15, p=0.006; r=0.13, p=0.001, respectively), and this was independent of paternal BMI. Multiple linear regression analysis revealed paternal insulin resistance to be a predictor of cord insulin concentrations, independently of maternal factors. Conclusion: Our results show an independent relationship between paternal insulin resistance and cord insulin concentrations. This is consistent with heritability of insulin resistance from father to offspring and a compensatory increase in fetal insulin secretion, the latter occurring prenatally before the homeostatic feedback loop between glucose and insulin is established.

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Adoption of the UKNSPC recommended cut-off (>240 μmol/L) will not affect the detection rate of classical PKU, but will improve the PPV from 76% to 80%. The use of a lower cut-off (130 μmol/L) for reflex galactosaemia testing enables the timely identification of asymptomatic cases that benefit particularly from early treatment, without prompting any unnecessary clinical referrals or delaying any referrals. This intervention may reduce mortality in this vulnerable group.

BACKGROUND Each year in England, almost 10,000 parents are informed of their child’s positive newborn bloodspot screening result around 2-8 weeks after birth, depending on the condition. Communication of positive newborn bloodspot screening results is a subtle and skilful task, which demands thought, preparation and evidence to minimise potentially harmful negative sequelae. Evidence exists of variability in the content and the way the result is currently communicated which has the potential to lead to increased parental anxiety and distress. OBJECTIVE The main objective was to co-design interventions to improve delivery of positive newborn bloodspot screening results to families. METHODS The principles of Experience-based Co-design were used with seventeen health care professionals employed in three National Health Service Trusts in England and 21 parents; 13 mothers and 8 fathers of 14 children recruited from the same three National Health Service Trusts. Staff experiences were gathered via semi-structured interviews. Filmed, narrative interviews with parents were developed into a composite film. These data were used to identify priorities for improving communication of positive newborn bloodspot screening results to parents during firstly, separate parent and heath care professionals feedback events followed by joint parent and heath care professionals feedback events. Following this, parents and heath care professionals worked together via online co-design working groups to develop co-designed solutions and additions to existing processes. RESULTS Themes identified from the parent’s interviews included: impact of initial communication; parental reactions; attending the first clinic appointment; impact of staff communication strategies and skills; impact of diagnosis on family and friends; improvements to the communication of positive NBS results; and parents views of NBS. Themes identified from the staff interviews included: communication between health care professionals; process of communicating with the family; parent and family- centred care; availability of resources and challenges to effective communication. Three online co-design working groups were developed, each attended by 12-18 participants who had taken part in the parental or health care professionals’ interviews. The priorities included: changes to the NBS card; standardised laboratory proformas; standardised communication checklists; and an email / letter for providing reliable up to date condition specific information for parents following communication of the positive NBS result. CONCLUSIONS Variation in communication practices for positive NBS results continues to exist. This was influenced by many factors and has the potential to lead to negative sequelae from a parental perspective. Parents and health care professionals were able to successfully work together to identify priorities and develop potential solutions to improve communication of positive NBS results to parents. The adaptation of EBCD to include virtual methods could reduce costs associated with this methodology while also enabling the approach to be more responsive to health care professionals’ and patients’/parents’ busy schedules. CLINICALTRIAL ISRCTN 15330120 INTERNATIONAL REGISTERED REPORT RR2-10.1186/s40814-019-0487-5