The importance of intravenous glucose tolerance test glucose stimulus for the evaluation of insulin secretion.

For 100 years, the Intravenous glucose tolerance test (IVGTT) has been used extensively in researching the pathophysiology of diabetes mellitus and AIRg-the IVGTT-induced acute insulin response to the rapid rise in circulating glucose-is a key measure of insulin secretory capacity. For an effective evaluation of AIRg, IVGTT glucose loading should be adjusted for glucose distribution volume (gVOL) to provide an invariant, trend-free immediate rise in circulating glucose (ΔG0). Body weight-based glucose loads have been widely used but whether these achieve a trend-free ΔG0 does not appear to have been investigated. By analysing variation in AIRg, ΔG0 and gVOL with a range of IVGTT loads, both observed and simulated, we explored the hypothesis that there would be an optimum anthropometry-based IVGTT load calculation that, by achieving a trend-free ΔG0, would not compromise evaluation of AIRg as an index of beta cell function. Data derived from patient and research volunteer records for 3806 IVGTT glucose and insulin profiles. Among the non-obese, as gVOL rose, weight increased disproportionately rapidly. Consequently, the IVGTT glucose load needed for an invariant ΔG0 was progressively overestimated, accounting for 47% of variation in AIRg. Among the obese, ΔG0 was trend-free yet AIRg increased by 11.6% per unit body mass index, consistent with a more proportionate increase in weight with gVOL and a hyperinsulinaemic adaptation to adiposity-associated insulin resistance. Simulations further confirmed our hypothesis by demonstrating that a body surface area-based IVGTT load calculation could provide for a more generally invariant IVGTT ΔG0.

Optimizing type 1 diabetes after multiple daily injections and capillary blood monitoring: Pump or sensor first? A meta-analysis using pooled differences in outcome measures.

AIMS: Most people living with type 1 diabetes self-manage using multiple daily injection (MDI) insulin regimens and self-monitoring of blood glucose (SMBG). Continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) are adjuncts to education and support self-management optimization. The aim of this systematic review and meta-analysis was to assess which first-line technology is most effective. METHODS: Electronic databases (MEDLINE, EMBASE and WEB OF SCIENCE) were systematically searched from 1999 to September 2020. Randomized controlled trials comparing either CSII with MDI or CGM with SMBG in adults with type 1 diabetes were included. Data were extracted in duplicate by two reviewers, and were analysed to assess individual and overall treatment effect measures (PROSPERO registration: CRD42020149915). RESULTS: Glycated haemoglobin was significantly reduced for CGM when compared with SMBG [Cohen's d - 0.62 (95% CI -0.79 to -0.45)] and for CSII when compared with MDI [Cohen's d - 0.44 (95% CI -0.67 to -0.22)]. Rates of severe hypoglycaemia were significantly reduced with CGM compared with SMBG, but did not change for CSII when compared with MDI. Episodes of diabetic ketoacidosis were more likely to occur with CSII than MDI. Both CSII and CGM reduced glucose standard deviation, compared with MDI and SMBG respectively. CONCLUSIONS: Both CGM and CSII remain impactful interventions compared with SMBG and MDI but in adults with type 1 diabetes and in the contexts in which they have been studied, CGM might have a greater positive impact on glycaemic variability and severe hypoglycaemia than CSII, when added to MDI and SMBG. A head-to-head study, including patient reported outcomes, is required to explore these findings further.

Improved glycaemia during the Covid-19 pandemic lockdown is sustained post-lockdown and during the "Eat Out to Help Out" Government Scheme, in adults with Type 1 diabetes in the United Kingdom.

AIMS: The majority of studies report that the Covid-19 pandemic lockdown did not have a detrimental effect on glycaemia. We sought to explore the impact of lockdown on glycaemia and whether this is sustained following easing of restrictions. METHODS: Retrospective, observational analysis in adults and children with type 1 diabetes attending a UK specialist centre, using real-time or intermittently scanned continuous glucose monitoring. Data from the following 28-day time periods were collected: (i) pre-lockdown; (ii) during lockdown; (iii) immediately after lockdown; and (iv) a month following relaxation of restrictions (coinciding with Government-subsidised restaurant food). Data were analysed for times in glycaemic ranges and are expressed as median (IQR). RESULTS: 145 adults aged 35.5 (25.8-51.3) years with diabetes duration of 19.0 (7.0-29.0) years on multiple daily injections of insulin (60%) and continuous insulin infusion (40%) were included. In adults, % time in range (70-180mg/dL) increased during lockdown (60.2 (45.2-69.3)%) compared to pre-lockdown (56.7 (43.5-65.3)%; p<0.001). This was maintained in the post-lockdown time periods. Similarly, % time above range (>180mg/dL) reduced in lockdown compared to pre-lockdown (p = 0.01), which was sustained thereafter. In children, no significant changes to glycaemia were observed during lockdown. In multivariable analysis, a greater increase in %TIR 3.9-10mmol/L (70-180mg/dL) during lockdown was associated with higher levels of deprivation (coefficient: 4.208, 95% CI 0.588 to 7.828; p = 0.02). CONCLUSIONS: Glycaemia in adults improved during lockdown, with people from more deprived areas most likely to benefit. This effect was sustained after easing of restrictions, with government-subsidised restaurant eating having no adverse impact on glycaemia.

Increasing glycaemia is associated with a significant decline in HDL cholesterol in women with prediabetes in two national populations.

Internationally, studies have shown associations between lipids and glycemia; however, whether the link varies by gender and population has been rarely examined. We investigated relationships between glycemia and HDL- and Non-HDL-cholesterol and their modification by gender. We undertook a cross-sectional analysis from the National Health Examination Survey for Thailand (NHES-Thailand) and the Health Survey for England (HS-England) in adults aged 18-75 year. Glycaemia was assessed by FPG in Thailand and by HbA1c in the UK. In population- and gender-stratified analyses, the relationships between glycemia and lipids were explored. A total of 15,145 Thai and 3484 UK adults with blood measurement were included. The prevalences of prediabetes were: in NHES-Thailand, 16% (SE = 0.004), based on FPG (5.6 to < 7.0 mmol/L) and in HS-England, 19% (0.007) based on HbA1c (39 to < 48 mmol/mol). Increasingly abnormal glucose homeostasis was associated with increasing age, adiposity, SBP, proportion of antihypertensive and lipid-lowering agent use and with decreasing HDL-cholesterol. Independent of age, adiposity, smoking, alcohol, physical activity, and lipid and BP lowering drug use, increasing glycemia was associated with decreasing HDL-cholesterol specifically in women with prediabetes (NHES-Thailand, beta-coefficient - 0.07 (95% CI - 0.15, - 0.001) p = 0.04 and HS-England, - 0.03 (- 0.04, - 0.006) p = 0.01). In both populations, among those with prediabetes, increasing glycaemia is associated with an adverse, significant decline in HDL cholesterol, specifically in women. These adverse effects are apparent in widely-differing international populations.

Mortality Risk in Patients With Adrenal Insufficiency Using Prednisolone or Hydrocortisone: A Retrospective Cohort Study.

CONTEXT: Prednisolone has been recommended rather than hydrocortisone for glucocorticoid replacement in adrenal insufficiency due its longer duration of action and lower cost. OBJECTIVE: To determine mortality rates with prednisolone versus hydrocortisone. METHODS: In this observational study, we used data extracted from a UK primary care database (Clinical Practice Research Datalink) to measure the relative mortality of patients with primary and secondary adrenal insufficiency, who were treated with either prednisolone or hydrocortisone, and control individuals who were individually matched for age, sex, period, and place of follow-up. RESULTS: As expected, mortality in adrenal insufficiency irrespective of cause was increased, based on 5478 patients (4228 on hydrocortisone; 1250 on prednisolone) and 54 314 controls (41 934 and 12 380, respectively). Overall, the adjusted hazard ratio (HR) was similar with the 2 treatments (prednisolone, 1.76 [95% CI, 1.54-2.01] vs hydrocortisone 1.69 [1.57-1.82]; P = 0.65). This was also the case for secondary adrenal insufficiency. In primary disease (1405 on hydrocortisone vs 137 on prednisolone; 13 965 and 1347 controls, respectively), prednisolone users were older, more likely to have another autoimmune disease and malignancy, and less likely to have mineralocorticoid replacement. Nevertheless, after adjustment, the HR for prednisolone-treated patients remained higher than for those taking hydrocortisone (2.92 [2.19-3.91] vs 1.90 [1.66-2.16]; P = 0.0020). CONCLUSION: In primary but not in secondary adrenal insufficiency, mortality was higher with prednisolone. The study was large, but the number of prednisolone-treated patients was small, and they had greater risk factors. Nonetheless, the increased mortality associated with prednisolone persisted despite statistical adjustment. Further evidence is needed regarding the long-term safety of prednisolone as routine replacement.

Cardiovascular Disease in Patients With Primary and Secondary Adrenal Insufficiency and the Role of Comorbidities.

CONTEXT: Mortality studies have established that cardiovascular disease is the leading cause of death in patients with adrenal insufficiency and the risk is greater than that observed in individually matched controls. OBJECTIVE: Here we have performed a detailed analysis of cardiovascular morbidity and mortality, taking account of the role of comorbidities. METHODS: We performed a retrospective cohort study using the Clinical Practice Research Datalink (CPRD), a UK general practitioner database. The participant population comprised 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) compared with 67 564 individually matched controls, with and without adjustment for comorbidities (diabetes, hypertension, dyslipidemia, previous cardiovascular disease, and smoking). The main outcome measures were composite cardiovascular events recorded in the CPRD and cardiovascular mortality in participants with linked national mortality data. RESULTS: Hazard ratios (95% CI) for composite cardiovascular events in patients with adrenal insufficiency of any cause were 1.28 (1.20-1.36, unadjusted) and 1.07 (1.01-1.14, adjusted). Increased cerebrovascular events in patients with secondary adrenal insufficiency accounted for most of the increased hazard (1.53 [1.34-1.74, adjusted]) and were associated with cranial irradiation therapy. Cardiovascular mortality data were available for 3547 patients and 34 944 controls. The adjusted hazard ratio for ischemic heart disease mortality was 1.86 (1.25-2.78) for primary adrenal insufficiency and 1.39 (1.02-1.89) for secondary. CONCLUSION: Comorbidities largely accounted for the increased cardiovascular events but in secondary adrenal insufficiency, cerebrovascular events were independently increased and associated with irradiation treatment. However, the risk of cardiovascular mortality remained increased even following adjustment for comorbidities in both primary and secondary adrenal insufficiency.

Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency.

CONTEXT: Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations. OBJECTIVE: To compare mortality risk and causes of death in adrenal insufficiency with an individually matched reference population. METHODS: A retrospective cohort study was done using a UK general practitioner database (CPRD). A total of 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) were compared with 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcomes were all-cause and cause-specific mortality, and hospital admission from adrenal crisis. RESULTS: With follow-up of 40 799 and 406 899 person-years for patients and controls respectively, the hazard ratio (HR [95% CI]) for all-cause mortality was 1.68 [1.58-1.77]. HRs were greater in primary (1.83 [1.66-2.02]) than in secondary (1.52 [1.40-1.64]) disease; primary versus secondary disease (1.16 [1.03-1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15-7.46]). Adrenal crisis contributed to 10% of all deaths. In the first 2 years following diagnosis, the patients' mortality rate and hospitalization from adrenal crisis were higher than in later years. CONCLUSION: Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality.

A pragmatic and scalable strategy using mobile technology to promote sustained lifestyle changes to prevent type 2 diabetes in India and the UK: a randomised controlled trial.

AIMS/HYPOTHESIS: This randomised controlled trial was performed in India and the UK in people with prediabetes to study whether mobile phone short message service (SMS) text messages can be used to motivate and educate people to follow lifestyle modifications, to prevent type 2 diabetes. METHODS: The study was performed in people with prediabetes (n = 2062; control: n = 1031; intervention: n = 1031) defined by HbA1c ≥42 and ≤47 mmol/mol (≥6.0% and ≤6.4%). Participants were recruited from public and private sector organisations in India (men and women aged 35-55 years) and by the National Health Service (NHS) Health Checks programme in the UK (aged 40-74 years without pre-existing diabetes, cardiovascular disease or kidney disease). Allocation to the study groups was performed using a computer-generated sequence (1:1) in India and by stratified randomisation in permuted blocks in the UK. Investigators in both countries remained blinded throughout the study period. All participants received advice on a healthy lifestyle at baseline. The intervention group in addition received supportive text messages using mobile phone SMS messages 2-3 times per week. Participants were assessed at baseline and at 6, 12 and 24 months. The primary outcome was conversion to type 2 diabetes and secondary outcomes included anthropometry, biochemistry, dietary and physical activity changes, blood pressure and quality of life. RESULTS: At the 2 year follow-up (n = 2062; control: n = 1031; intervention: n = 1031), in the intention-to-treat population the HR for development of type 2 diabetes calculated using a discrete-time proportional hazards model was 0.89 (95% CI 0.74, 1.07; p = 0.22). There were no significant differences in the secondary outcomes. CONCLUSIONS/INTERPRETATION: This trial in two countries with varied ethnic and cultural backgrounds showed no significant reduction in the progression to diabetes in 2 years by lifestyle modification using SMS messaging. TRIAL REGISTRATION: The primary study was registered on www.ClinicalTrials.gov (India, NCT01570946; UK, NCT01795833). FUNDING: The study was funded jointly by the Indian Council for Medical Research and the UK Medical Research Council.

Effects of tibolone or continuous combined oestradiol and norethisterone acetate on lipids, high-density lipoprotein subfractions and apolipoproteins in postmenopausal women in a two-year, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effects of (a) tibolone, (b) continuous combined oestrogen plus progestogen and (c) placebo on plasma lipid and lipoprotein markers of cardiovascular risk in healthy postmenopausal women. STUDY DESIGN: Randomized, single-centre, placebo-controlled, double-blind study. PATIENTS: One hundred and one postmenopausal women were randomized (1:1:1) into one of three groups taking daily 2.5 mg tibolone, continuous oral oestradiol-17ß 2 mg plus norethisterone acetate 1 mg daily (E2 /NETA) or placebo. MAIN OUTCOME MEASURES: Fasting serum lipid, lipoprotein and apolipoprotein concentrations measured at baseline and after 6, 12 and 24 months of treatment. RESULTS: Both tibolone and E2 /NETA lowered plasma total cholesterol concentrations relative to placebo. With tibolone, high-density lipoprotein cholesterol (HDL-C) was reduced (-27% at 24 months, P < .001), the greatest effect being in the cholesterol-enriched HDL2 subfraction (-40%, P < .001). Tibolone's effect on HDL concentrations was also apparent in the principal HDL protein component, apolipoprotein AI (-29% at 24 months, P < .001). However, there was no significant effect of tibolone on low-density or very low-density lipoprotein cholesterol (LDL-C and VLDL-C, respectively). By contrast, the greatest reduction in cholesterol with E2 /NETA was in LDL-C (-22% at 24 months, P = .008). E2 /NETA reduced HDL-C to a lesser extent than tibolone (-12% at 24 months, P < .001). Effects on HDL apolipoproteins were similarly diminished relative to tibolone. E2 /NETA had no effect on VLDL-C or on the protein component of LDL, apolipoprotein B. CONCLUSION: Tibolone reduces serum HDL. E2 /NETA reduces LDL cholesterol but not apolipoprotein B, suggesting decreased cholesterol loading of LDL. Any impact these changes may have on CVD risk needs further investigation.

A natural mutation in Pisum sativum L. (pea) alters starch assembly and improves glucose homeostasis in humans.

Elevated postprandial glucose (PPG) is a significant risk factor for non-communicable diseases globally. Currently, there is a limited understanding of how starch structures within a carbohydrate-rich food matrix interact with the gut luminal environment to control PPG. Here, we use pea seeds (Pisum sativum) and pea flour, derived from two near-identical pea genotypes (BC1/19RR and BC1/19rr) differing primarily in the type of starch accumulated, to explore the contribution of starch structure, food matrix and intestinal environment to PPG. Using stable isotope 13C-labelled pea seeds, coupled with synchronous gastric, duodenal and plasma sampling in vivo, we demonstrate that maintenance of cell structure and changes in starch morphology are closely related to lower glucose availability in the small intestine, resulting in acutely lower PPG and promotion of changes in the gut bacterial composition associated with long-term metabolic health improvements.

Hyperglycemia recognised in early pregnancy is phenotypically type 2 diabetes mellitus not gestational diabetes mellitus: a case control study.

Objective: Gestational diabetes mellitus is defined as "diabetes recognized in the second or third trimester that is not clearly overt diabetes". Evidence relating to women with hyperglycemia early in pregnancy is limited. We aimed to evaluate women diagnosed with hyperglycemia early in pregnancy (eGDM) and compared them to those with pregestational established type 2 diabetes mellitus (T2DM) and gestational diabetes diagnosed routinely at 24-28-week gestation (rtGDM) to determine if the length of exposure to hyperglycemia adversely affected outcomes.Methods: Forty consecutive women with eGDM who attended a multidisciplinary antenatal clinic were reviewed. Two separate BMI-matched control groups were identified, recognized pregestational T2DM (n = 80) and rtGDM (n = 80). Baseline demographics and outcomes were compared.Results: A higher proportion of women in the eGDM and T2DM group required insulin and the incidence of hypertensive disorders was similarly increased compared with the rtGDM group (88.6, 77.0 versus 8.1%, p < .001 and 42.5%, 37.5 versus 12.5% p < .001, respectively). The proportion of infants born small for gestational age varied (eGDM 11.1%, T2DM 13.0%, and rtGDM 2.5%, p=.049). Postpartum, 7.5% of eGDM women were diagnosed with T2DM versus 1.3% in the rtGDM group (p<.001).Conclusions: These novel data demonstrate that the length of exposure to glucose adversely affects materno-foetal outcomes independent of maternal adiposity.

Individual and diabetes presentation characteristics associated with partial remission status in children and adults evaluated up to 12 months following diagnosis of type 1 diabetes: An ADDRESS-2 (After Diagnosis Diabetes Research Support System-2) study analysis.

AIMS: People with recently-diagnosed type 1 diabetes mellitus (T1D) may undergo a transient period of glycaemic control with less exogenous insulin. Identification of predictors of this 'remission' could inform a better understanding of glycaemic control. METHODS: Participants in the ADDRESS-2 study were included who had 1 or 2 assessments of remission status (coincident insulin dose and HbA1c measurement, with remission defined by ≤0.4 units insulin/kg-body-weight/day with HbA1c < 53 mmol/mol). Demographic and clinical presentation characteristics were compared according to remission status and predictors of remission were explored by logistic regression analysis. RESULTS: 1470 first and 469 second assessments of remission status were recorded within 12 months of diagnosis of T1D. Step increases in the probability of remission were identified at age-at-diagnosis 20 years and 3 months after diagnosis (both p < 0.001). Among those aged < 20 years, remission was associated with male gender (p = 0.02), no ketoacidosis (p = 0.02) and fewer than 2 symptoms at presentation (p = 0.004). None of these characteristics predicted remission in those aged ≥ 20 years. In the subgroup with two assessments, transition to remission was independently associated with first remission assessment in months 1-2 post-diagnosis (p = 0.01), with age-at-diagnosis ≥ 20 years (p = 0.01) and, in those aged < 20 years, with an early HbA1c of <57 mmol/mol. Adiposity, ethnicity, autoantibody status and other autoimmune disease were unrelated to remission. CONCLUSIONS: For those diagnosed before 20 years of age, males, ketoacidosis-free, with fewer symptoms and low early HbA1c were more likely to experience remission, but remission was most likely in anyone aged ≥ 20 at diagnosis.

Metabolic health and vascular complications in type 1 diabetes.

AIMS: Optimal glycaemic control benefits risk of microvascular and macrovascular complications in type 1 diabetes (T1DM) but the importance of other components of metabolic health is less certain, particularly in the context of routine clinical practice. METHODS: Data for this cross-sectional analysis derived from a database covering inner North West London adult diabetes clinics. People with T1DM and with complete information for height, weight, blood pressure and serum high and low-density lipoprotein cholesterol (HDL-c and LDL-c) and triglyceride concentration measurements were included. RESULTS: Among the 920 participants, those with complications were older and had longer duration of diabetes but had similar HbA1c to people without complications. Systolic hypertension and low HDL-c were independently associated with complications. From having 0 risk factors, the prevalence of micro and macrovascular disease increased with increasing number of risk factors. Relative to those with ≥1 risk factor, those with 0 risk factors (n = 179) were at lower risk of retinopathy (OR 0.6 (0.4-0.9), p = 0.01) and nephropathy [OR 0.1 (0.04-0.3), p = 0.002], independent of individual characteristics. CONCLUSIONS: In routine clinical management of T1DM, associations between lipid and blood pressure risk factors and prevalent micro and macrovascular disease remain, implying that more intensive risk factor management may be beneficial.

Independent relationships between bone mineral density, regional body fat and insulin sensitivity in white males.

BACKGROUND: Adiposity and insulin sensitivity may affect bone mineral density (BMD), but the confounding effect of weight hinders discrimination of independent associations. We explored whether regional fat masses and insulin sensitivity are independently related to BMD. MATERIALS AND METHODS: Relationships between total and regional body fat, insulin sensitivity and measures of BMD in 8 different regions were evaluated in a cross section of 590 generally healthy, white males, 274 of whom received measurement of insulin sensitivity (Si) using the intravenous glucose tolerance test. Measurements included total, android and gynoid fat and lean body mass and regional BMDs by dual-energy X-ray absorptiometry. Linear regression analyses were combined in a mediation analysis to explore associations with each regional BMD. RESULTS: Weight correlated positively with total fat mass (R2  = 0.67, P < 0.001) and negatively with Si (R2  = 0.14, P < 0.001). Body composition measures were consistently positively related to BMD in all regions except lumbar and thoracic spine. Accounting for body weight rendered negative majority of associations between total and regional fat masses and BMDs. An independent association between android fat and spine BMD was particularly apparent. Si was positively associated with total and limb BMD (P < 0.01) specifically among exercisers. Accounting for Si diminished the associations of total fat (negative) and lean body mass (positive) with total and limb BMD. CONCLUSION: Android fat is independently negatively associated with spine BMD. Among those taking exercise, increased insulin sensitivity is associated with higher limb BMD and may underlie positive associations between lean body mass and BMD.

Cardiometabolic risk factors in Thai individuals with prediabetes treated in a high-risk, prevention clinic: Unexpected relationship between high-density lipoprotein cholesterol and glycemia in men.

AIMS/INTRODUCTION: Relationships between cardiometabolic risk and glycemia have rarely been studied in people under clinical evaluation and treatment for cardiometabolic risk and with prediabetes. We investigated relationships between glycemia and cardiometabolic risk factors in clinic participants with prediabetes. MATERIALS AND METHODS: This was a cross-sectional analysis of data collected at a center in Thailand. Clinic attendees were at high risk of diabetes or cardiovascular disease, with hemoglobin A1c (HbA1c) 39-<48 mmol/mol or fasting plasma glucose (FPG) 5.6-<7.0 mmol/L. The relationships between glycemia and cardiometabolic risk factors were explored. RESULTS: Of 357 participants, two or more insulin resistance-related metabolic disturbances were present in 84%; 61% took a statin and 75% an antihypertensive agent. Independently of age, sex, adiposity, medication use, possible non-alcoholic fatty liver disease and sex-glycemia interaction, neither FPG nor HbA1c were associated with variation in any other cardiometabolic risk factors. High-density lipoprotein cholesterol decreased with HbA1c in women (female-HbA1c interaction, P = 0.03) but, unexpectedly, increased with FPG in men (male-FPG interaction, P = 0.02). CONCLUSIONS: Overall, in Thai people treated for high cardiometabolic risk and with prediabetes defined by FPG and/or HbA1c, neither FPG nor HbA1c were associated with other cardiometabolic risk factors. However, according to sex, high-density lipoprotein cholesterol showed the expected relationship with glycemia in women, but the reverse in men.

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.

BACKGROUND: Type 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%; 42-47 mmol/mol) in the UK and India. METHODS/DESIGN: This is a randomised, controlled trial with participants followed up for 2 years. 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 24 months). In the UK there are 4 visits after screening (0, 6, 12 and 24 months). Questionnaires (EQ-5D, RPAQ, Transtheoretical Model of Behavioural Change, and food frequency (UK)/24 h 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-ß; acceptability of SMS; dietary parameters; physical activity and quality of life. DISCUSSION: The 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 REGISTRATION: ClinicalTrials.gov ; NCT01570946 , 4th April 2012 (India); NCT01795833 , 21st February 2013 (UK).

The effects of kisspeptin on ß-cell function, serum metabolites and appetite in humans.

AIMS: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. MATERIALS AND METHODS: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m-2 ), we compared the effects of 1 nmol kg-1 h-1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human ß-cell line (EndoC-ßH1 cells). RESULTS: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. CONCLUSIONS: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions.

The post-trial analysis of the Indian SMS diabetes prevention study shows persistent beneficial effects of lifestyle intervention.

AIMS: We had shown that mobile phone based text messaging was an effective tool to deliver lifestyle changes among Asian Indian men with a 36% relative risk reduction in incident diabetes over two years. The present analysis investigated whether beneficial effects of intervention on diabetes prevention persisted for an additional three years after withdrawal of active intervention. METHODS: The primary two year randomized controlled trial (2010-2012) compared lifestyle changes with use of automated text messaging reminders in the intervention (n = 271) versus standard care advice (n = 266) at baseline. At the end of the study, both groups received additional advice on lifestyle changes by a trained dietician. Participants free of diabetes (n = 394) were invited three years later to ascertain the sustained effect of intervention. The primary outcome was incidence of type 2 diabetes. This trial is registered with ClinicalTrials.gov,number NCT02848547. RESULTS: During the mean follow-up of 5 years, 346 out of 394 (87.8%) men were reviewed. Incidence of diabetes was reduced by 30% in the intervention group, with declining gap between-group differences over time (Kaplan-Meier analysis). Significant improvement in dietary adherence occurred in the intervention group at 2nd and 5th year follow up (trend χ2 = 21.35, p < 0.0001). Cox regression analysis showed that the 5th year incidence of diabetes was significantly reduced in the intervention group. Higher body mass index and 2 h plasma glucose at 24 months increased the incidence of diabetes. CONCLUSIONS: Sustained reduction in incident diabetes was apparent after cessation of active lifestyle intervention. This was possibly associated with continuing practice of improved lifestyle.

Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort.

OBJECTIVES: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive. DESIGN: Observational cohort study. SETTING: 146 mainly secondary care centres across England and Wales. PARTICIPANTS: 3312 people aged ≥5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%. MAIN OUTCOME MEASURES: Autoantibody status and characteristics at presentation. RESULTS: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01). CONCLUSIONS: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes. TRIAL REGISTRATION NUMBER: ISRCTN66496918; Pre-results.