The leptin to adiponectin ratio (LAR) is reduced by sleeve gastrectomy in adults with severe obesity: a prospective cohort study.

Bariatric surgery is known to reduce leptin and increase adiponectin levels, but the influence of sleeve gastrectomy on the leptin: adiponectin ratio (LAR), a measure of insulin sensitivity and cardiovascular risk, has not previously been described. We sought to determine the influence of sleeve gastrectomy on LAR in adults with severe obesity.In a single centre prospective cohort study of adults undergoing laparoscopic sleeve gastrectomy over a four-month period in our unit, we measured LAR preoperatively and 12 months after surgery. Of 22 patients undergoing sleeve gastrectomy, 17 (12 females, 12 with type 2 diabetes) had follow-up LAR measured at 12.1 ± 1 months. Mean body weight decreased from 130.6 ± 30.8 kg to 97.6 ± 21.6 kg, body mass index (BMI) from 46.9 ± 7.8 to 35.3 ± 7.2 kg m-2 and excess body weight from 87.5 ± 31.3 to 41.3 ± 28.8% (all p < 0.001). The reduction in leptin from 40.7 ± 24.9 to 30.9 ± 30.5 ng/ml was not significant (p = 0.11), but adiponectin increased from 4.49 ± 1.6 to 8.93 ± 6.36 µg/ml (p = 0.005) and LAR decreased from 8.89 ± 4.8 to 5.26 ± 6.52 ng/µg (p = 0.001), equivalent to a 70.9% increase in insulin sensitivity. The correlation with the amount of weight lost was stronger for LAR than it was for leptin or adiponectin alone. In this single-centre, interventional prospective cohort, patients undergoing laparoscopic sleeve gastrectomy had a substantial reduction in their LAR after 12 months which was proportional to the amount of weight lost. This may indicate an improvement in insulin sensitivity and a reduction in cardiovascular risk.

SGLT2 inhibitor-induced euglycaemic diabetic ketoacidosis may be due to abrupt, severe and transient impaired glucose sensing in susceptible individuals with a hitherto unrecognised beta cell SGLT variant.

Euglycaemic diabetic ketoacidosis (EDKA) is a rare complication of treatment with SGLT2 inhibitors in patients with type 2 diabetes. Uncertainty remains about its precise mechanistic basis, but the physiological derangement is acute and profound, yet reversible with cessation of the drug. It is reminiscent of other "non type 1" presentations with DKA such as ketosis prone diabetes, except that glucose levels are usually normal. Impaired beta cell glucose sensing that mimicked a state of hypoglycaemia could theoretically lead to abrupt and transient cessation of insulin secretion. GLUT2 mediates glucose sensing in beta cells. In other tissues such as enterocytes, GLUT2 mediated glucose transport is controlled by SGLT1. Although the affinity of SGLT1 for SGLT2 inhibitors is low, hypothetically a rare variant within the SGLT family with a hitherto unrecognised role in GLUT2 mediated glucose sensing might have an affinity for the SGLT2 inhibitor ligand and thus give rise to acute, severe but reversible euglycaemic DKA in susceptible patients.

Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis.

BACKGROUND: Neurosarcoidosis is a rare and aggressive variant of systemic sarcoidosis which may result in hypothalamic-pituitary dysfunction. We report a case of hypothalamic hypopituitarism secondary to neurosarcoidosis complicated by adipsic diabetes insipidus (ADI). Initiation of anti-tumour necrosis factor-α (TNF-α) therapy resulted in both radiological disease remission and recovery of osmoregulated thirst appreciation after 3 months. CASE SUMMARY: A 22-year-old man was referred to the endocrinology service with profound weight gain, polyuria and lethargy. Biochemical testing confirmed anterior hypopituitarism while posterior pituitary failure was confirmed by hypotonic polyuria responding to desmopressin. Magnetic resonance imaging (MRI) demonstrated extensive hypothalamic infiltration; neurosarcoidosis was confirmed histologically after excisional cervical lymph node biopsy. Osmoregulated thirst appreciation was normal early in the disease course despite severe hypotonic polyuria. However, subsequent subjective loss of thirst appreciation and development of severe hypernatraemia in the setting of normal cognitive function indicated onset of ADI. MANAGEMENT: Clinical management involved daily weighing, regular plasma sodium measurement, fixed daily fluid intake and oral desmopressin. We initiated immunosuppressive therapy with pulsed intravenous anti-TNF-α therapy (infliximab) after multidisciplinary team consultation. OUTCOME: Infliximab therapy resulted in successful radiological disease remission and complete recovery of osmoregulated thirst appreciation. This was confirmed by subjective return of thirst response and maintenance of plasma sodium in the normal range in the absence of close biochemical monitoring.

Glycaemic control is harder to achieve than blood pressure or lipid control in Irish adults with type 1 diabetes.

We sought to determine the attainment of targets for glycaemic control and vascular risk reduction in an Irish cohort of T1DM adults. Of 797 patients (53% male, mean age 40.3 ± 14.8 years, HbA1c 8.5 ± 1.6% (69.6 ± 17.8 mmol mol(-1))), 15%, 68% and 62% achieved targets for HbA1c, blood pressure and LDL cholesterol, respectively.

Reduced insulin requirements during participation in the DAFNE (dose adjustment for normal eating) structured education programme.

Dose adjustment for normal eating (DAFNE) is a well-established structured education programme for patients with type 1 diabetes. We conducted a retrospective analysis of insulin dose changes associated with DAFNE training. Our results show significant reductions in total, quick acting and basal insulin doses in patients undergoing DAFNE training.

The effects of aerobic exercise on metabolic risk, insulin sensitivity and intrahepatic lipid in healthy older people from the Hertfordshire Cohort Study: a randomised controlled trial.

AIMS/HYPOTHESIS: We sought to determine the effect of an aerobic exercise intervention on clustered metabolic risk and related outcomes in healthy older adults in a single-centre, explanatory randomised controlled trial. METHODS: Participants from the Hertfordshire Cohort Study (born 1931-1939) were randomly assigned to 36 supervised 1 h sessions on a cycle ergometer over 12 weeks or to a non-intervention control group. Randomisation and group allocation were conducted by the study co-ordinator, using a software programme. Those with prevalent diabetes, unstable ischaemic heart disease or poor mobility were excluded. All data were collected at our clinical research facility in Cambridge. Components of the metabolic syndrome were used to derive a standardised composite metabolic risk score (zMS) as the primary outcome. Trial status: closed to follow-up. RESULTS: We randomised 100 participants (50 to the intervention, 50 to the control group). Mean age was 71.4 (range 67.4-76.3) years. Overall, 96% of participants attended for follow-up measures. There were no serious adverse events. Using an intention-to-treat analysis, we saw a non-significant reduction in zMS in the exercise group compared with controls (0.07 [95% CI -0.03, 0.17], p = 0.19). However, the exercise group had significantly decreased weight, waist circumference and intrahepatic lipid, with increased aerobic fitness and a 68% reduction in prevalence of abnormal glucose metabolism (OR 0.32 [95% CI 0.11-0.92], p = 0.035) compared with controls. Results were similar in per-protocol analyses. CONCLUSIONS/INTERPRETATION: Enrolment in a supervised aerobic exercise intervention led to weight loss, increased fitness and improvements in some but not all metabolic outcomes. In appropriately screened older individuals, such interventions appear to be safe. TRIAL REGISTRATION: Controlled-trials.com ISRCTN60986572 FUNDING: Medical Research Council.

Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals.

AIMS/HYPOTHESIS: Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults. METHODS: Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic-euglycaemic clamp studies in 1,226 EGIR RISC participants. RESULTS: The LAR was highly correlated with HOMA-S in men (r = -0.58, p = 4.5 x 10(-33) and r = -0.65, p = 1.1 x 10(-66) within the Ely and EGIR RISC study cohorts, respectively) and in women (r = -0.51, p = 2.8 x 10(-36) and r = -0.61, p = 2.5 x 10(-73)). The LAR was also strongly correlated with the clamp M/I value (r = -0.52, p = 4.5 x 10(-38) and r = -0.47, p = 6.6 x 10(-40) in men and women, respectively), similar to correlations between HOMA-S and the M/I value. CONCLUSIONS/INTERPRETATION: The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.

Obesity in Irish youth: epidemiology and implications.

The worldwide epidemic of type 2 diabetes has been paralleled by a marked increase in the prevalence of obesity, particularly in younger people. This will contribute significantly to the future burden of cardiovascular disease. Complex environmental and genetic factors contribute to obesity and related metabolic disorders. These disorders are now manifesting in younger age groups, including children. Recent studies have described the clinical and metabolic characteristics of these children. A solution to the obesity crisis will need to be co-ordinated, multi-faceted and well resource.

Altered respiratory function is associated with increased metabolic risk, independently of adiposity, fitness and physical activity.

AIMS: Reduced lung function is associated with an adverse metabolic risk profile, even after adjusting for body fatness. However, previous observations may have been confounded by aerobic fitness and physical activity. This study aimed to examine the association between lung function and both metabolic risk and insulin resistance in a cohort of White British adults with a family history of Type 2 diabetes, and to explore the extent to which these associations are independent of body fatness, aerobic fitness (VO(2max)) and objectively measured physical activity. METHODS: Adults (n = 320, mean age 40.4 +/- 6.0 years) underwent measurement of physical activity energy expenditure (PAEE), spirometry [forced expiratory volume in 1 s (FEV(1))] and forced vital capacity (FVC), aerobic fitness (predicted VO(2max)), and anthropometric and metabolic status at baseline and again after 1 year (n = 257) in the ProActive trial. Clustered metabolic risk was calculated by summing standardized values for triglycerides, fasting insulin, fasting glucose, blood pressure and the inverse of high-density lipoprotein-cholesterol. A cross-sectional analysis using linear regression with repeated measures was performed. RESULTS: Both FEV(1) and FVC were inversely and statistically significantly associated with metabolic risk and insulin resistance after adjusting for age, sex, smoking status, height, PAEE and fitness. The associations with metabolic risk remained significant after adjusting for measures of body fatness, but those with insulin resistance did not. CONCLUSIONS: Reduced lung function was associated with increased metabolic risk in this cohort of carefully characterized at-risk individuals. This association was independent of overall and central body fatness, objectively measured physical activity and aerobic fitness.

Elevated blood pressure in overweight and obese Irish children.

BACKGROUND: The Irish childhood obesity epidemic, one of the highest ranking internationally, represents a major threat to public health. We sought to perform a retrospective observational study of a clinic based cohort of obese Irish children. METHODS: Clinical data relating to gender, age, height, weight, body mass index and blood pressure were analysed, from 206 children referred to a paediatric endocrine referral centre over a 15-year period for assessment of obesity. RESULTS: Younger patients tended to have a higher standardised body mass index at initial presentation; 92% of boys and 96% of girls referred were obese (age-related BMI >/= 95th percentile). Boys (51%) and girls (49%) had initial blood pressure measurements in the hypertensive range. There was a correlation between the degree of obesity and systolic blood pressure, particularly in boys. CONCLUSIONS: Obese Irish children present with significant long-term health risks, including hypertension at baseline.

Genomic variants at the PINK1 locus are associated with transcript abundance and plasma nonesterified fatty acid concentrations in European whites.

The purpose of this study was to characterize associations between PINK1 genotypes, PINK1 transcript levels, and metabolic phenotypes in healthy adults and those with type 2 diabetes (T2D). We measured PINK1 skeletal muscle transcript levels and 8 independent PINK1 single nucleotide polymorphisms (SNPs) in a cohort of 208 Danish whites and in a cohort of 1701 British whites (SNPs and metabolic phenotypes only). Furthermore, we assessed the effects of PINK1 transcript ablation in primary adipocytes using RNA interference (RNAi). Six PINK1 SNPs were associated with PINK1 transcript levels (P<0.04 to P<0.0001). Obesity modified the association between PINK1 transcript levels and T2D risk (interaction P=0.005); transcript levels were inversely related with T2D in obese (n=105) [odds ratio (OR) per sd increase in expression levels=0.44; 95% confidence interval (CI): 0.23, 0.84; P=0.013] but not in nonobese (n=103) (OR=1.20; 95% CI: 0.82, 1.76; P=0.34) individuals. In the British cohort, several PINK1 SNPs were associated with plasma nonesterified fatty acid concentrations. Nominal genotype associations were also observed for fasting glucose, 2-h glucose, and maximal oxygen consumption, although these were not statistically significant after correcting for multiple testing. In primary adipocytes, Pink1 knockdown affected fatty acid binding protein 4 (Fabp4) expression, indicating that PINK1 may influence substrate metabolism. We demonstrate that PINK1 polymorphisms are associated with PINK1 transcript levels and measures of fatty acid metabolism in a concordant manner, whereas our RNAi data imply that PINK1 may indirectly influence lipid metabolism.

Adverse metabolic profiles in a cohort of obese Irish children.

BACKGROUND: The metabolic characteristics of obese Irish children are not well defined. We prospectively examined the relationship between the degree of obesity and glucose metabolism, insulin sensitivity and suspected non-alcoholic steatohepatosis (NASH) in a pilot study of obese Irish children. METHODS: We measured height, weight, body mass index (BMI), blood pressure, waist and hip circumference in 18 participants (mean age 15.5 years). Fasting blood glucose, insulin, lipid profile and alanine aminotransferase (ALT) concentrations were also measured. A standard 75 g oral glucose tolerance test was performed and insulin sensitivity was derived from this using a mathematical model--oral glucose insulin sensitivity. RESULTS: There were significant associations between the degree of obesity, insulin sensitivity and markers of liver steatosis. For example, when adjusted for pubertal status, there were significant associations between standardized BMI and insulin sensitivity (regression coefficient, beta = -70.1, P = 0.018) and ALT (beta = 20.7, P = 0.007). CONCLUSION: This study suggests that the degree of obesity is associated with lower insulin sensitivity and possible NASH in obese Irish children.

Propylthiouracil induced C-ANCA positive agranulocytosis complicating Graves' thyrotoxicosis in pregnancy.

BACKGROUND: Thionamide induced agranulocytosis is associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) in some patients. This poses a particular challenge when it occurs during pregnancy. AIMS: To report a case of a 31-year-old woman with Graves' disease who presented at 11 weeks gestation with propylthiouracil induced agranulocytosis. METHODS: After cessation of propylthiouracil the patient developed recurrent thyrotoxicosis, and underwent an elective subtotal thyroidectomy at 23 weeks gestation. RESULTS: The patient required postoperative thyroxine replacement therapy. Subsequent pregnancy was uneventful and she delivered a healthy baby boy at 41 weeks gestation. As part of our routine work up for agranulocytosis we measured C-ANCA levels, which were significantly elevated. CONCLUSION: This case highlights the association of propylthiouracil induced ANCA positivity and agranulocytosis. Second trimester subtotal thyroidectomy was safe and effective in treating this pregnant patient's thyrotoxicosis.

Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training.

AIMS/HYPOTHESIS: Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. MATERIALS AND METHODS: Anthropometric parameters and maximum volume of oxygen utilisation (VO(2max)) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic-euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. RESULTS: Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO(2max) increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. CONCLUSIONS/INTERPRETATION: Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention.