General practitioner and nurse experiences of type 2 diabetes management and prescribing in primary care: a qualitative review following the introduction of funded SGLT2i/GLP1RA medications in Aotearoa New Zealand.

AIM: To explore the views of general practitioners (GPs) and nurses on type 2 diabetes (T2D) management, including the use of recently funded T2D medications in New Zealand (NZ) and their perceived barriers to providing optimal care. BACKGROUND: T2D is a significant health concern in NZ, particularly among Maori and Pacific adults. Characterised by prolonged hyperglycaemia, T2D is generally a progressive condition requiring long-term care. METHODS: Semi-structured interviews were conducted between July and December 2022 with 21 primary care clinicians (10 GPs and 11 nurses/nurse prescribers) from nine different general practice clinics across the Auckland and Waikato regions of NZ. Framework analysis was conducted to identify common themes in clinicians' perceptions and experiences with T2D management. FINDINGS: Three themes were identified: health-system factors, new medications, and solution-based approaches. Lack of clinician time, healthcare funding, staff shortages, and burn-out were identified as barriers to T2D management under health-system factors. The two newly funded medications, empagliflozin and dulaglutide, were deemed to be a positive change for T2D care in that they improved patient satisfaction and clinical outcomes, but several clinicians were hesitant to prescribe these medications. Participants suggested that additional education and specialist diabetes support would be helpful to inform optimal medication prescribing and that better use of a multi-disciplinary team (clinical and support staff) could support T2D care by reducing workload, addressing cultural gaps in healthcare delivery, and reducing burnout. An improved primary care work environment, including appropriate professional development to support prescribing of new medications and the value of collaboration with a non-regulated workforce, may be required to facilitate optimal T2D management in primary care. Future research should focus on interventions to increase support for both clinical teams and patients while adopting a culturally appropriate approach to increase patient satisfaction and improve health outcomes.

Diabetes treatment satisfaction among a multi-ethnic Aotearoa New Zealand population with uncontrolled type 2 diabetes mellitus.

AIMS: To assess whether diabetes treatment satisfaction differs by ethnicity among participants with insufficient glycaemic control of type 2 diabetes mellitus in a clinical trial involving additional oral diabetes medications. Patient satisfaction is used as an indicator of healthcare quality. However, data on patients' diabetes treatment satisfaction in the context of insufficient glycaemic control is limited. METHODS: Individuals with type 2 diabetes and an HbA1c of 58-110mmol/mol (7.5-12.5%) were recruited across Aotearoa New Zealand to participate in an 8-month randomised crossover study of vildagliptin and pioglitazone as add-on therapy to metformin and/or sulfonylurea. Participants completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at baseline pre-randomisation. Treatment satisfaction scores were compared between ethnic groups and other characteristics using the analysis of variance and linear regression. Perceived hyper- and hypoglycaemia were summarised separately. RESULTS: Between February 2019 and March 2020, 346 participants (41% women, 32% Pacific peoples, 23% Maori, 26% European) completed the DTSQ. Mean (SD) age was 57.5 (10.9) years, diabetes duration was 9 (6.3) years and HbA1c was 75 (12)mmol/mol (9.0[3.2]%). At study entry, 40% were receiving monotherapy for diabetes. Treatment satisfaction was rated highly, with a score of 29(6) (interquartile range 25-33). Pacific peoples and older people reported greater treatment satisfaction than other groups (p<0.001). CONCLUSIONS: Diabetes treatment satisfaction was high, particularly among Pacific peoples, despite suboptimal glycaemic control and insufficient glucose-lowering therapy.

"Prescribing for the whole person": A qualitative study exploring prescribing pharmacist views on type 2 diabetes management in New Zealand.

BACKGROUND: Pharmacist prescribers have comprehensive pharmacotherapy knowledge that can be useful for management of complex health conditions such as type 2 diabetes, yet the number of pharmacist prescribers working in New Zealand primary care is low. AIM: To explore the experiences of pharmacist prescribers in supporting type 2 diabetes management in New Zealand primary care. METHODS: Qualitative research design using semi-structured interviews with six pharmacist prescribers working in NZ primary care. Thematic analysis guided this study and themes were finalised with the wider research team. RESULTS: Three major themes were identified: team approach, health inequity and the role of a pharmacist prescriber. This study found that pharmacist prescribers may improve health equity by providing advanced pharmacotherapy knowledge within a wider primary care team to support complex patient needs and understanding the wider social determinants of health that impact effective diabetes management. Participants reportedly had more time to spend with patients (than GPs or nurses) and could also contribute to improving health outcomes by directly educating and empowering patients. CONCLUSION: The views of pharmacist prescribers have seldom been explored and this study suggests that their role may be under-utilised in primary care. In particular, pharmacist prescribers can provide specialist prescribing (and often mobile) care, and may contribute to improving health outcomes and reducing inequity when used as part of a multi-disciplinary team.

Stratified glucose-lowering response to vildagliptin and pioglitazone by obesity and hypertriglyceridemia in a randomized crossover trial.

Background: Understanding which group of patients with type 2 diabetes will have the most glucose lowering response to certain medications (which target different aspects of glucose metabolism) is the first step in precision medicine. Aims: We hypothesized that people with type 2 diabetes who generally have high insulin resistance, such as people of Maori/Pacific ethnicity, and those with obesity and/or hypertriglyceridemia (OHTG), would have greater glucose-lowering by pioglitazone (an insulin sensitizer) versus vildagliptin (an insulin secretagogue). Methods: A randomised, open-label, two-period crossover trial was conducted in New Zealand. Adults with type 2 diabetes, HbA1c>58mmol/mol (>7.5%), received 16 weeks of either pioglitazone (30mg) or vildagliptin (50mg) daily, then switched to the other medication over for another 16 weeks of treatment. Differences in HbA1c were tested for interaction with ethnicity or OHTG, controlling for baseline HbA1c using linear mixed models. Secondary outcomes included weight, blood pressure, side-effects and diabetes treatment satisfaction. Results: 346 participants were randomised (55% Maori/Pacific) between February 2019 to March 2020. HbA1c after pioglitazone was lower than after vildagliptin (mean difference -4.9mmol/mol [0.5%]; 95% CI -6.3, -3.5; p<0.0001). Primary intention-to-treat analysis showed no significant interaction effect by Maori/Pacific vs other ethnicity (1.5mmol/mol [0.1%], 95% CI -0.8, 3.7), and per-protocol analysis (-1.2mmol/mol [0.1%], 95% CI -4.1, 1.7). An interaction effect (-4.7mmol/mol [0.5%], 95% CI -8.1, -1.4) was found by OHTG status. Both treatments generated similar treatment satisfaction scores, although there was greater weight gain and greater improvement in lipids and liver enzymes after pioglitazone than vildagliptin. Conclusions: Comparative glucose-lowering by pioglitazone and vildagliptin is not different between Maori/Pacific people compared with other New Zealand ethnic groups. Presence of OHTG predicts greater glucose lowering by pioglitazone than vildagliptin. Clinical trial registration: www.anzctr.org.au, identifier (ACTRN12618001907235).

Effects of nutritional supplementation during pregnancy on early adult disease risk: follow up of offspring of participants in a randomised controlled trial investigating effects of supplementation on infant birth weight.

BACKGROUND: Observational evidence suggests that improving fetal growth may improve adult health. Experimental evidence from nutritional supplementation trials undertaken amongst pregnant women in the less developed world does not show strong or consistent effects on adult disease risk and no trials from the more developed world have previously been reported. OBJECTIVE: To test the hypothesis that nutritional supplementation during pregnancy influences offspring disease risk in adulthood. DESIGN: Clinical assessment of a range of established diseases risk markers in young adult offspring of 283 South Asian mothers who participated in two trials of nutritional supplementation during pregnancy (protein/energy/vitamins; energy/vitamins or vitamins only) at Sorrento Maternity Hospital in Birmingham UK either unselected or selected on the basis of nutritional status. RESULTS: 236 (83%) offspring were traced and 118 (50%) of these were assessed in clinic. Protein/energy/vitamins supplementation amongst undernourished mothers was associated with increased infant birthweight. Nutritional supplementation showed no strong association with any one of a comprehensive range of markers of adult disease risk and no consistent pattern of association with risk across markers in offspring of either unselected or undernourished mothers. CONCLUSIONS: We found no evidence that nutritional supplements given to pregnant women are an important influence on adult disease risk however our study lacked power to estimate small effects. Our findings do not provide support for a policy of nutritional supplementation for pregnant women as an effective means to improve adult health in more developed societies.

The relationship between serum TSH and free T4 in older people.

The frequency distribution of serum thyroid stimulating hormone (TSH) shows a skewed pattern that may change with age. The set point of the hypothalamic-pituitary-thyroid axis for an individual is thought to be genetically determined and has been described as a log-linear relationship of serum TSH to free thyroxine (T4); however, the validity of this hypothesis has yet to be established in older people. The aim of the study was to describe the relationship between serum TSH and free T4 in older people and define factors influencing this relationship. We conducted a cross-sectional, observational study of thyroid function in a community population of older subjects over 65 years of age. The relationship between serum TSH and free T4 was not linear as previously described, but is best described as a fourth-order polynomial. Both gender and smoking status affected the relationship. This suggests that more complex modelling is required when investigating the hypothalamic-pituitary-thyroid axis.

Can we interpret serum thyroglobulin results?

Thyroglobulin (Tg) is a tumour marker for differentiated thyroid cancer. Interpretation requires a knowledge of the current thyrotropin (TSH) concentration as secretion is TSH-dependent. While a raised serum Tg may be indicative of residual or recurrent thyroid cancer, trauma to the thyroid (e.g. surgical, biopsy or due to radioiodine treatment) also causes an increase. Tg may be measured when TSH is suppressed and also following recombinant TSH (rhTSH) stimulation. Interpretation of results in pregnancy and in children is discussed. Assay bias and interference by endogenous Tg antibodies (Abs) are the main confounders in the interpretation of results. Although there is an international standard for Tg, there are large differences in results and yet there are few assay-specific clinical decision limits. Patients should therefore be monitored with the same assay. Endogenous TgAbs may cause false-negative interference in immunometric assays and may cause false-positive results in radioimmunoassay. Although the measurement of TgAbs has been advocated for predicting interference, it is now clear that interference can still occur when TgAbs have not been detected, the effect being TgAb-assay-specific. Approaches to identifying those samples where there may be interference are discussed. The laboratory should have a protocol for the investigation of possible interferences and data on the bias of the Tg assay that they use. An appreciation of the clinical uses of the service is required as an understanding by endocrinologists, oncologists and endocrine surgeons of the analytical limitations of the service.

The relationship between serum TSH and free T4 in older people.

The frequency distribution of serum thyroid stimulating hormone (TSH) shows a skewed pattern that may change with age. The set point of the hypothalamic-pituitary-thyroid axis for an individual is thought to be genetically determined and has been described as a log-linear relationship of serum TSH to free thyroxine (T4); however, the validity of this hypothesis has yet to be established in older people. The aim of the study was to describe the relationship between serum TSH and free T4 in older people and define factors influencing this relationship. We conducted a cross-sectional, observational study of thyroid function in a community population of older subjects over 65 years of age. The relationship between serum TSH and free T4 was not linear as previously described, but is best described as a fourth-order polynomial. Both gender and smoking status affected the relationship. This suggests that more complex modelling is required when investigating the hypothalamic-pituitary-thyroid axis.

Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey.

CONTEXT: Population-based screening has been advocated for subclinical thyroid dysfunction in the elderly because the disorder is perceived to be common, and health benefits may be accrued by detection and treatment. OBJECTIVE: The objective of the study was to determine the prevalence of subclinical thyroid dysfunction and unidentified overt thyroid dysfunction in an elderly population. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey of a community sample of participants aged 65 yr and older registered with 20 family practices in the United Kingdom. EXCLUSIONS: Exclusions included current therapy for thyroid disease, thyroid surgery, or treatment within 12 months. OUTCOME MEASURE: Tests of thyroid function (TSH concentration and free T4 concentration in all, with measurement of free T3 in those with low TSH) were conducted. EXPLANATORY VARIABLES: These included all current medical diagnoses and drug therapies, age, gender, and socioeconomic deprivation (Index of Multiple Deprivation, 2004). ANALYSIS: Standardized prevalence rates were analyzed. Logistic regression modeling was used to determine factors associated with the presence of subclinical thyroid dysfunction. RESULTS: A total of 5960 attended for screening. Using biochemical definitions, 94.2% [95% confidence interval (CI) 93.8-94.6%] were euthyroid. Unidentified overt hyper- and hypothyroidism were uncommon (0.3, 0.4%, respectively). Subclinical hyperthyroidism and hypothyroidism were identified with similar frequency (2.1%, 95% CI 1.8-2.3%; 2.9%, 95% CI 2.6-3.1%, respectively). Subclinical thyroid dysfunction was more common in females (P < 0.001) and with increasing age (P < 0.001). After allowing for comorbidities, concurrent drug therapies, age, and gender, an association between subclinical hyperthyroidism and a composite measure of socioeconomic deprivation remained. CONCLUSIONS: Undiagnosed overt thyroid dysfunction is uncommon. The prevalence of subclinical thyroid dysfunction is 5%. We have, for the first time, identified an independent association between the prevalence of subclinical thyroid dysfunction and deprivation that cannot be explained solely by the greater burden of chronic disease and/or consequent drug therapies in the deprived population.

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

BACKGROUND: Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. METHODS: We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. RESULTS: A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. CONCLUSIONS: Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].).

Phylogenetic lineages of invasive and colonizing strains of serotype III group B Streptococci from neonates: a multicenter prospective study.

This study compares the phylogenetic lineages of invasive serotype III group B streptococci (GBS) to those of colonizing strains in order to determine lineages associated with invasive disease. Isolates from 29 infants with early-onset disease (EOD) and from 196 colonized infants, collected in a prospective, multicenter study, were assigned a sequence type (ST) by multilocus sequence typing. Overall, 54.5% of the isolates were in the ST-19 complex, and 40.4% were in the ST-17 complex. Invasive strains were more likely to be in the ST-17 complex than were colonizing strains (59% versus 38%, P = 0.03). After we adjusted for potential confounders, the ST-17 complex was more likely to be associated with EOD than were other lineages (odds ratio = 2.51, 95% confidence interval = 1.02 to 6.20). These data support the hypothesis that ST-17 complex GBS are more virulent than other serotype III GBS.

Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1alpha mutation carriers.

OBJECTIVE: Patients with diabetes due to hepatocyte nuclear factor (HNF)-1alpha mutations have beta-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-1alpha 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-1alpha 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 beta-cell deficiency with reduced insulinogenic index (53.5 [31.5-90.9] vs. 226.0 [126.0-407.1], SD [range], P < 0.001) and area under the curve for insulin (P < 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 = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects (P = 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 = 0.002). The seven subjects with diabetes all showed glycosuria. CONCLUSIONS: We conclude that marked beta-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1alpha 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 >8.4 mmol/l.

Level of maternal IgG anti-group B streptococcus type III antibody correlated with protection of neonates against early-onset disease caused by this pathogen.

The present study estimates the level of maternal immunoglobulin (Ig) G anti-group B streptococcus (GBS) type III required to protect neonates against early-onset disease (EOD) caused by this pathogen. Levels of maternal serum IgG anti-GBS type III, measured by enzyme-linked immunosorbent assay, in 26 case patients (neonates with EOD caused by GBS type III) and 143 matched control subjects (neonates colonized by GBS type III who did not develop EOD) of > or = 34 weeks gestation were compared. The probability of EOD decreased with increasing levels of maternal IgG anti-GBS type III (P = .01). Neonates whose mothers had > or = 10 microg/mL IgG anti-GBS type III had a 91% lower risk for EOD, compared with those whose mothers had levels of < 2 microg/mL. A vaccine that induces IgG anti-GBS type III levels of > or = 10 microg/mL in mothers can be predicted to offer a significant degree of protection against EOD caused by this pathogen.

Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue.

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.

Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes.

Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 +/- 87 pg/ml (mean +/- SEM); 1 nM insulin, 1414.0 +/- 89 pg/ml; 1 microM insulin, 1797 +/- 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 +/- 35 pg/ml; insulin, 1 microM insulin plus RSG, 1019 +/- 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.

Genetic cause of hyperglycaemia and response to treatment in diabetes.

BACKGROUND: Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1alpha diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity. METHODS: We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1alpha mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance. FINDINGS: Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4.7 vs 0.9 mmol/L, p=0.0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0.002). Patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups. INTERPRETATION: The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1alpha diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.

Variants in the aromatase gene and on the Y-chromosome are not associated with adult height or insulin resistance in a UK population.

OBJECTIVE: To assess the association of polymorphisms in the aromatase gene (CYP19) and on the Y-chromosome, with adult height and insulin resistance in a UK Caucasian population, after a recent report indicated these variants explain 4 cm of adult male height variation. PATIENTS AND DESIGN: We performed an association study using 917 healthy UK Caucasian subjects from the Exeter Family Study, an ongoing consecutive-birth cohort. Our study had > 85% (95% for the CYP19 variant; 85% for the Y variant) power to detect the association suggested by the previous study. MEASUREMENTS: Subjects'CYP19 genotype were determined using tetra-primer PCR, and the Y-chromosome variant genotype was identified using a restriction fragment length polymorphism (RFLP) method. Trained research nurses were responsible for measurement of height. Fasting insulin concentration was determined by an immunoenzymometric assay. RESULTS: We did not find any evidence for an effect of the CYP19 polymorphism or Y-RFLP on adult height (P > 0.83 for both variants). In addition, there was no evidence for an effect on insulin resistance in a subset of 416 subjects (P > 0.46). CONCLUSION: We have not confirmed the initial observation in a larger replication cohort. Our results highlight the importance of replicating initial results from genetic association studies.

Low-dose growth hormone inhibits 11 beta-hydroxysteroid dehydrogenase type 1 but has no effect upon fat mass in patients with simple obesity.

GH has potent effects on adipocyte biology, stimulating lipolysis but also promoting preadipocyte proliferation. In addition, GH, acting through IGF-I, inhibits 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), which converts the inactive glucocorticoid, cortisone (E), to active cortisol (F) in adipose tissue. Although F is an essential requirement for adipocyte differentiation, it also inhibits preadipocyte proliferation. We hypothesized that inhibition of 11 beta-HSD1 activity in adipose tissue by GH may alter fat tissue mass through changes in local F concentrations. We conducted a randomized, double-blind, placebo-controlled study using low-dose GH (Genotropin 0.4 mg/d) for 8 months in 24 patients with obesity. Although GH treatment significantly raised IGF-I, we were unable to demonstrate significant differences in body composition or metabolic profiles between GH- and placebo-treated groups. In addition, there was no alteration in total fat mass over time in the GH-treated group [total fat mass 41.0 +/- 3.0 vs. 41.3 +/- 3.4 kg (8 months), mean +/- SE, P = ns]. However, in comparison with baseline values, systolic blood pressure increased (119 +/- 3 vs. 130 +/- 4 mm Hg, P < 0.05 vs. baseline) and serum F/E ratio decreased (6.1 +/- 0.5 vs. 3.9 +/- 0.5, P < 0.05 vs. baseline) in the GH-treated group only. Furthermore, although the urinary tetrahydrometabolites of F/E ratio fell in the GH-treated group, it rose in the placebo group (mean ratio change, -0.13 +/- 0.05 vs. +0.09 +/- 0.09, GH vs. placebo, P = 0.07). Treatment with low-dose GH in obesity fails to alter fat mass despite a significant elevation in IGF-I and a shift in the global set point of E to F conversion consistent with inhibition of 11 beta-HSD1.

Intrapartum antibiotic prophylaxis 1: relative effects of recommended antibiotics on gram-negative pathogens.

OBJECTIVE: To assess whether the antibiotic chosen for intrapartum antibiotic prophylaxis affects the subsequent exposure of the neonate to ampicillin-resistant gram-negative bacteria. METHODS: We performed a randomized clinical trial of ampicillin versus penicillin for intrapartum antibiotic prophylaxis. Genital tract cultures for Enterobacteriaceae were obtained at study entry and 8-36 hours postpartum. Organisms were isolated, identified, and tested for ampicillin susceptibility. RESULTS: The ampicillin (n = 175) and penicillin (n = 177) groups, respectively, did not differ in rates of ampicillin-resistant Escherichia coli at entry (25% versus 22%, P =.57) or postpartum (36% versus 38%, P =.64). Similarly, groups did not differ in rates of ampicillin-resistant Enterobacteriaceae at entry (38% versus 32%, P =.23) or postpartum (51% versus 55%, P =.46). However, postpartum culture rates of resistant Escherichia coli were higher than entry culture rates for both the ampicillin (36% versus 25%, P =.026) and penicillin (38% versus 22%, P <.001) groups. Postpartum culture rates of resistant Enterobacteriaceae were also higher than entry culture rates for both the ampicillin (51% versus 38%, P <.001) and penicillin (55% versus 32%, P <.001) groups. Results were similar when considering only women who received two or more doses and no additional antibiotics. CONCLUSION: Intrapartum antibiotic prophylaxis with either ampicillin or penicillin increases exposure of neonates to ampicillin-resistant Enterobacteriaceae.