Desmond G. Johnston

Loss of beta cell function as fasting glucose increases in the non-diabetic range

Aims/hypothesisOur aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline.MethodsPlasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis.ResultsAs fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42xa0mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0xa0mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG.Conclusions/interpretationThe range of FPG over which progressive loss of the first-phase response begins may be as low as 5.0 to 5.4xa0mmol/l, with late-phase insulin responses declining at FPG concentrations above 6.0xa0mmol/l.

The effects of prolonged growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults.

OBJECTIVE Short‐term GH replacement in hypopituitary adults increases bone turnover; data on the consequences of longer‐term GH treatment are limited. We report on the effects of 12–18 months of GH replacement treatment with biosynthetic human GH on bone metabolism and bone mass in hypopituitary adults.

The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes.

Aims/hypothesisWe assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM).Materials and methodsGlucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2–22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and following pregnancy.ResultsImpaired glucose regulation or diabetes by WHO criteria were present in 37% of women with previous GDM (diabetes in 17%), especially in those of African-Caribbean and Asian-Indian origin (50 and 44%, respectively vs 28% in European, p=0.009). BMI, waist circumference, diastolic blood pressure, fasting triglyceride and insulin levels, and insulin resistance by homeostatic model assessment (HOMA), were increased following GDM (p<0.001 for all, vs control subjects). Where glucose regulation was normal following GDM, basal insulin secretion (by HOMA) was high (p<0.001 vs control subjects). Irrespective of glucose regulation in pregnancy, Asian-Indian origin was associated with high triglyceride and low HDL cholesterol levels, and African-Caribbean with increased waist circumference, blood pressure, and insulin levels, together with insulin resistance and low triglyceride concentrations. Nonetheless, the GDM-associated features were consistent within each ethnic group. The metabolic syndrome by International Diabetes Federation criteria was present in 37% of women with previous GDM, especially in non-Europeans (Asian-Indian 49%, African-Caribbean 43%, European 28%, p=0.001), and in 10% of controls.Conclusions/interpretationFollowing GDM, abnormal glucose regulation and the metabolic syndrome are common, especially in non-European women, indicating a need for diabetes and cardiovascular disease prevention strategies.

Magnetic resonance imaging of the normal pituitary gland using ultrashort TE (UTE) pulse sequences (REV 1.0)

IntroductionThe purpose of this study was to examine the normal pituitary gland in male subjects with ultrashort echo time (TE) pulse sequences, describe its appearance and measure its signal intensity before and after contrast enhancement.Methods Eleven male volunteers (mean age 57.1xa0years; range 36–81xa0years) were examined with a fat-suppressed ultrashort TE (=u20090.08xa0ms) pulse sequence. The studies were repeated after the administration of intravenous gadodiamide. The MR scans were examined for gland morphology and signal intensity before and after enhancement. Endocrinological evaluation included baseline pituitary function tests and a glucagon stimulatory test to assess pituitary cortisol and growth hormone reserve.ResultsHigh signal intensity was observed in the anterior pituitary relative to the brain in nine of the 11 subjects. These regions involved the whole of the anterior pituitary in three subjects, were localised to one side in two examples and were seen inferiorly in three subjects. Signal intensities relative to the brain increased with age, with a peak around the sixth or seventh decade and decreasing thereafter. Overall, the pituitary function tests were considered to be within normal limits and did not correlate with pituitary gland signal intensity.ConclusionThe anterior pituitary shows increased signal intensity in normal subjects when examined with T1-weighted ultrashort TE pulse sequences. The cause of this increased intensity is unknown, but fibrosis and iron deposition are possible candidates. The variation in signal intensity with age followed the temporal pattern of iron content observed at post mortem. No relationship with endocrine status was observed.

Metabolic effects of pharmacological adrenergic blockade in phaeochromocytoma

Twelve‐hour hormonal and metabolic profiles were performed in a 68‐year‐old woman with a benign adrenal phaeochromocytoma (a) prior to adrenergic blockade, (b) after the establishment of pharmacological alpha‐blockade with phenoxybenzamine, (c) after combined alpha and beta‐blockade with phenoxybenzamine and propranolol, and (d) after successful surgery and withdrawal of medication. Pretreatment, (a) vs (d), significant elevations (12‐h mean ± SD) were observed In the concentrations of noradrenaline (44·9 ± 14 ± 4 vs 2·3 ± 0.7 nmol/l, p > 0·01), glucose (6·9 ± 1·9 vs 5·0 ± 1·0 mmol/l, p > 0·05), glycerol (0·22 ± 0.02 vs 0·07 ± 0·01 mmol/l, p > 0·01), non‐esterifled fatty acids (0·71 ± 0·28 vs 0·34 ± 0·08 mmol/l, p>0·01), and total ketone bodies (0·08 ± 0·03 vs 0·03 ± 0·02 mmol/l, p > 0·01). Alpha‐blockade, (b) vs (a), was associated with an increase in noradrenaline levels (P > 0·01) but not with any significant alterations in intermediary metabolite concentrations. Following the establishment of combined alpha and beta‐blockade, (c) vs (b), plasma noradrenaline returned to its pretreatment level while the concentrations of glycerol, fatty acids and ketone bodies were normalized. A completely physiological 12‐h blood glucose profile, however, was observed only post‐operatively. No significant differences were observed in mean plasma insulin levels between the four studies. These results indicate impaired regulation of multiple aspects of carbohydrate, lipid and ketone body metabolism in our patient. Alpha‐blockade did not ameliorate the abnormalities in any aspect of intermediary metabolism and was associated with an increase in noradrenaline levels. Combined alpha and beta‐blockade effectively normalized lipolysis and ketone body metabolism but did not fully correct the abnormality in glucose metabolism.

Metabolic effects of Troglitazone in patients with diet-controlled type 2 diabetes

Backgroundu2002 In order to study the mechanisms of action of Troglitazone (TGZ) in vivo in Type 2 diabetes, its effects were studied on glucose metabolism, lipolysis and very low‐density lipoprotein (VLDL) apolipoprotein B100 (apoB) kinetics.

Growth hormone and the microvascular complications of diabetes

The basis for the hypothesis that growth hormone is a permissive factor in the pathogenesis of diabetic microvascular complications is a weak one. The best way forward in this research will be to devise a pharmacological method of suppressing growth hormone secretion in diabetic subjects.

Protocol for a clinical trial of text messaging in addition to standard care versus standard care alone in prevention of type 2 diabetes through lifestyle modification in India and the UK

BackgroundType 2 diabetes is a serious clinical problem in both India and the UK. Adoption of a healthy lifestyle through dietary and physical activity modification can help prevent type 2 diabetes. However, implementing lifestyle modification programmes to high risk groups is expensive and alternative cheaper methods are needed. We are using a short messaging service (SMS) programme in our study as a tool to provide healthy lifestyle advice and an aid to motivation. The aim of the study is to assess the efficacy and user acceptability of text messaging employed in this way for people with pre-diabetes (HbA1c 6.0% to ≤6.4%; 42–47xa0mmol/mol) in the UK and India.Methods/designThis is a randomised, controlled trial with participants followed up for 2xa0years. After being screened and receiving a structured education programme for prediabetes, participants are randomised to a control or intervention group. In the intervention group, text messages are delivered 2–3 times weekly and contain educational, motivational and supportive content on diet, physical activity, lifestyle and smoking. The control group undergoes monitoring only. In India, the trial involves 5 visits after screening (0, 6, 12, 18 and 24xa0months). In the UK there are 4 visits after screening (0, 6, 12 and 24xa0months). Questionnaires (EQ-5D, RPAQ, Transtheoretical Model of Behavioural Change, and food frequency (UK)/24xa0h dietary recall (India)) and physical activity monitors (Actigraph GT3X+ accelerometers) are assessed at baseline and all follow-up visits. The SMS acceptability questionnaires are evaluated in all follow-up visits. The primary outcome is progression to type 2 diabetes as defined by an HbA1c of 6.5% or over(India) and by any WHO criterion(UK). Secondary outcomes are the changes in body weight, body mass index, waist circumference, blood pressure, fasting plasma glucose; lipids; proportion of participants achieving HbA1c ≤6.0%; HOMA-IR; HOMA-β; acceptability of SMS; dietary parameters; physical activity and quality of life.DiscussionThe study is designed to assess the efficacy of tailored text messaging in addition to standard lifestyle advice to reduce the progression from prediabetes to type 2 diabetes in the two different countries.Trial registrationClinicalTrials.gov; NCT01570946, 4th April 2012 (India); NCT01795833, 21st February 2013 (UK).