Ovarian hyperstimulation syndrome without gonadotropin stimulation: an unusual response to a GnRH agonist.

Ovarian hyperstimulation syndrome (OHSS) is a well-known iatrogenic complication of ovarian stimulation with gonadotropins. We present the case of a woman in her 30s who developed OHSS without the administration of gonadotropins. She was due to undergo intracytoplasmic sperm injection (ICSI) for primary subfertility. After taking a gonadotropin-releasing hormone (GnRH) receptor agonist for 3 weeks, she presented with abdominal pain, nausea and bloating. She was diagnosed with moderate to severe OHSS, requiring management as an inpatient.Investigations included a pelvic ultrasound scan showing an enlarged ovary, serum oestradiol >30 000 pmol/L and an MRI of the brain with an incidental finding of a 5 mm pituitary microadenoma.She recovered rapidly and was referred for endocrinology evaluation and multidisciplinary team discussion. The OHSS was felt to be explained by an unusual 'flare' response to a GnRH agonist. A further ICSI cycle with an antagonist protocol is planned.

Maternal Graves Disease Postthyroidectomy With Fetal Thyrotoxicosis and Goiter.

Fetal thyrotoxicosis is a rare condition with high morbidity and mortality. It may complicate pregnancies in women with a history of Graves disease (GD) when transplacental passage of maternal TSH receptor antibodies stimulate the fetal thyroid gland and cause hyperthyroidism. We report the case of a 34-year-old woman with a history of GD and prior thyroidectomy, where fetal thyrotoxicosis at 21 weeks of gestation was suspected due to prenatal ultrasound findings of cardiac failure and fetal goiter. She was treated with high-dose carbimazole and followed closely by a multidisciplinary team. Her baby was delivered in good condition at 34 weeks' gestation and developed hyperthyroidism in the days after birth, which was successfully treated medically. This case highlights the importance of awareness of the condition among women with a history of GD, as well as the necessity for prompt diagnosis and treatment of this complex disease.

Clinical Outcomes Following a Change in Gestational Diabetes Mellitus Diagnostic Criteria Due to the COVID-19 Pandemic: A Case-Control Study.

BACKGROUND: Due to COVID-19, many centres adopted a change to the diagnosis of GDM. METHODS: A case-control study of antenatal patients between 1 April and 30 June in 2019 and 2020 looking at detection rates of GDM, use of medication, obstetric, and fetal outcomes. RESULTS: During COVID-19, the rate of positive GDM tests approximately halved (20% (42/210) in 2020 vs. 42.2% (92/218) in 2019, (p < 0.01)) with higher rates of requirement for insulin at diagnosis (21.4% (2020) vs. 2.2% (2019); p < 0.01), and at term (31% (2020) vs. 5.4% (2019); p < 0.01). and metformin at diagnosis (4.8% (2020) vs. 1.1% (2019); p < 0.01), and at term (14.3% (2020) vs. 7.6% (2019) p < 0.01), with no differences in birth outcomes. CONCLUSIONS: There was likely an underdiagnosis of GDM while women at a higher risk of hyperglycaemia were correctly identified. The GTT should be maintained as the gold-standard test where possible, with provisions made for social distancing during testing if required.

Cystic Fibrosis-Related Diabetes Mellitus and Pregnancy: A Retrospective Study.

INTRODUCTION: Cystic fibrosis-related diabetes mellitus (CFRDM) is becoming a more common issue in pregnancy care as the life expectancy of females living with cystic fibrosis has improved, with an increasing number of pregnancies in this population. Despite the Republic of Ireland having the highest incidence of cystic fibrosis globally, there is limited Irish data on pregnancy outcomes for those with CFRDM. This study aimed to retrospectively review maternal and foetal outcomes of pregnancies affected by maternal CFRDM. METHODS: The patient records of all women with CFRDM who attended the National Maternity Hospital Dublin for obstetric care between 2015 and 2019 were retrospectively reviewed. RESULTS: A search of patient records identified 15 pregnancies in 12 women with CFRDM during the study period. CFRDM was diagnosed pre-conception in ten of the 15 pregnancies. Median neonatal weight at birth was lower in women with CFRDM diagnosed pre-conception compared to women diagnosed during pregnancy (2.8 vs. 3.02 kg). The median weight gain in women with CFRDM diagnosed pre-conception was 10.9 kg compared to 11.9 kg for those diagnosed during pregnancy. The majority of women (62.5%) with CFRDM diagnosed pre-conception delivered via caesarean section. Admission for CF exacerbations during pregnancy in women with CFRDM diagnosed pre-conception was very common (87.5%) compared with 75% of those diagnosed during their pregnancy. CONCLUSION: Women diagnosed with CFRDM were likely to require caesarean section, to be treated with insulin, and to be frequently admitted to hospital for CF exacerbations. Our review highlights the importance of good glucose control, stable cystic fibrosis before pregnancy and a multidisciplinary team approach.

Treatment-resistant hypertension in a post-transplant patient with cystic fibrosis: a rare case of phaeochromocytoma.

SUMMARY: Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications - amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182-867) as well as elevated metanephrines (MN) of 793 pmol/L (61-377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient's blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential. LEARNING POINTS: Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1-1.0% of all secondary hypertension cases. Secondary causes should be investigated in cases where: Patient is presenting <20 years of age or >50 years of age, There is refractory hypertension, or There is serious end-organ damage present. Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms. Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour. Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration. There is a possibility of relapse so high-risk patients require life-long follow-up.

Pre-Gestational Diabetes and Pregnancy Outcomes.

INTRODUCTION: Pre-gestational, type 1 and type 2 diabetes are associated with adverse neonatal outcomes and increased rates of emergency caesarean sections. METHODS: We studied pregnancy outcomes associated with pre-gestational diabetes in 174 women who attended the National Maternity Hospital in Dublin, Ireland, between 2015 and 2017. RESULTS: Fifty women (28.6%) had type 2 diabetes mellitus, and 124 women (71.4%) had type 1 diabetes mellitus. Women with type 2 diabetes mellitus were older (36 vs. 34 years, p 0.02) and had a higher BMI (32.6 vs. 26.2 kg/m2, p 0.00). Duration of diabetes mellitus in type 1 and type 2 was 15.7 and 5.7 years, respectively, and mean HbA1c in type 2 diabetes mellitus at booking was 44.5 mmol/mol (6.2%) and in type 1 diabetes mellitus was 56.3 mmol/mol (7.3%). Forty women (32%) with type 1 diabetes mellitus used continuous subcutaneous insulin infusion. In our cohort, 45.4% had a caesarean delivery. Offspring of patients with multiple dose injections were lighter (3.58 kg) than infants of continuous subcutaneous insulin infusion-treated patients (3.75 kg). More emergency caesarean sections were observed in the continuous subcutaneous insulin infusion group than in the group treated with multiple dose injections (37.5% vs. 28.5%), while the elective caesarean section rate was higher in the multiple dose injection group (17.8% vs. 12.5%). Women treated with continuous subcutaneous insulin infusion had a higher rate of miscarriage (25% vs. 19%) with more congenital malformations (10% vs. 2.3%). CONCLUSIONS: Women in our study with pre-gestational diabetes were overweight, were older and had long-standing diabetes mellitus. Our patients with type 2 diabetes had a higher BMI, were older, had a shorter duration of diabetes mellitus and had better diabetes control compared to women with type 1 diabetes. Women treated with continuous subcutaneous insulin infusion had a higher rate of miscarriage with more congenital malformations. The initial inadequate diabetes control was significantly improved during pregnancy.

Post-transplant diabetes mellitus associated with heart and lung transplant.

BACKGROUND: The incidence of post-transplant diabetes (PTDM) is variable primarily due to a lack of standardised diagnostic criteria. AIM: This study aimed to assess the incidence of PTDM in heart and lung transplant (HLT) patients and to review if the management of these patients is in accordance with the 2014 American Society of Transplantation guidelines. METHODS: This was a retrospective study in the Mater Misericordiae University Hospital, Dublin, Ireland. Data was collected from the patients who had undergone HLT. RESULTS: All patients who had a heart and/or lung transplant between 2005 and 2017 were identified. The majority of our patients had lung 111 (53.9%), heart 94 (45.6%) and combined heart/lung 1(0.5%) transplants. A total of 174 (84.5%) patients were screened for diabetes pre-transplantation. Two hundred five (99.9%) patients were screened for PTDM post-surgery. The cumulative incidence for PTDM was 19.4% (40/206). All patients with PTDM were on prednisolone, 32 (80%) on tacrolimus and 4 (10%) on cyclosporine. CONCLUSIONS: The cumulative incidence of post-transplant diabetes in our cohort was 19.4%. The majority of the patients were screened before and after transplant for glucose abnormality. The authors recommend that all patients should be managed in a multidisciplinary setting including transplant physicians, endocrinlogist, diabetes nurse specialists, transplant nurses and dietitians.

Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis.

AIMS/HYPOTHESIS: Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or 'lipokine') to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans. METHODS: Plasma NEFA concentration and composition were determined in non-diabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort at baseline (n = 1234) and after a 3 year follow-up (n = 924). Glucose tolerance, insulin secretion and beta cell function were assessed during an OGTT. Whole-body insulin sensitivity was measured by a hyperinsulinaemic-euglycaemic clamp (M/I) and OGTT (oral glucose insulin sensitivity index [OGIS]). The liver insulin resistance index was calculated using clinical and biochemical data. Body composition including fat mass was determined by bioelectrical impedance. RESULTS: Circulating palmitoleate was proportional to fat mass (r = 0.21, p < 0.0001) and total NEFA levels (r = 0.19, p < 0.0001). It correlated with whole-body insulin sensitivity (M/I: standardised regression coefficient [std. ß] = 0.16, p < 0.0001), liver insulin resistance (std. ß = -0.14, p < 0.0001), beta cell function (potentiation: std. ß = 0.08, p = 0.045) and glucose tolerance (2 h glucose: std. ß = -0.24, p < 0.0001) after adjustment for age, sex, BMI, adiposity and other NEFA. High palmitoleate concentrations prevented the decrease in insulin sensitivity associated with excess palmitate (p = 0.0001). In a longitudinal analysis, a positive independent relationship was observed between changes in palmitoleate and insulin sensitivity over time (std. ß = 0.07, p = 0.04). CONCLUSIONS/INTERPRETATION: We demonstrated that plasma palmitoleate is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals. These results support the role of palmitoleate as a beneficial lipokine released by adipose tissue to prevent the negative effects of adiposity and excess NEFA on systemic glucose metabolism.

The prevalence and incidence of thyroid dysfunction in patients with diabetes - a longitudinal follow-up study.

BACKGROUND: Thyroid dysfunction (TD) occurs in 13.4% of diabetic patients, which has prompted recommendations for annual thyroid screening in patients with diabetes. However, recommendations for annual screening should be based on disease incidence rather than prevalence. METHODS: In 1997-1998, seven hundred and thirty patients (618 type 2 diabetes, 55% male; 112 type 1 diabetes, 47% male) were sequentially screened for TD. The 639 patients with normal thyroid function were followed from 1999 to 2006, with annual thyroid function tests. RESULTS: A total of 21/112 (19%) with type 1 diabetes (T1DM) and 70/618 (11%) with type 2 diabetes (T2DM) had TD. TD was more frequent in females (p < 0.05) and T1DM (p = 0.04). The mean annual rate of conversion to abnormal tests was 2.1%. At 8 years, there were 100 new cases of TD representing 15.6% of the cohort (17 T1DM and 83 T2DM). TD was more frequent in females (p < 0.05), but there was no difference in the incidence of new TD between T1DM and T2DM (p = 0.39). CONCLUSIONS: Our data confirms the high prevalence of TD in diabetic patients, in concordance with the results from other series. We found only 25 treatable cases of new thyroid disease from 639 patients in the 8-year follow-up, less than 0.5% per year. The low incidence of treatable thyroid disease challenges the need for annual screening for thyroid abnormalities in patients with type 2 diabetes.

Microvascular diabetes complications in a specialist young adult diabetes service.

BACKGROUND AND AIMS: The provision of medical care to young adults with type 1 diabetes mellitus is challenging. The aim of this study was to determine the rates of microvascular complications and their progression among patients with type 1 diabetes mellitus attending a specialist young adult diabetes service in Ireland. METHODS: A retrospective review of 62 (male 56.5%) patients with type 1 diabetes mellitus attending the young adult diabetes service at our institution was undertaken. Data was recorded across two time points, clinic registration and at 5 years following initial contact. RESULTS: The mean ± SD age at first attendance was 17.4 ± 2.0 years. Mean ± SD duration of diabetes was 6.3 ± 3.9 years with most patients treated using multiple daily insulin injections (75.8%). diabetic retinopathy rate at first attendance was 17.7% and after 5 years was 37.1% (p = 0.003). The majority of cases were background retinopathy. The prevalence of diabetic kidney disease was 6.4% and this remained unchanged at follow-up. Mean ± SD HbA1c improved from 76.1 ± 22.4 mmol/mol (9.1 ± 4.2%) to 69.1 ± 14.9 mmol/mol (8.5 ± 3.5%), p = 0.044. Duration of diabetes was the only clinical variable associated with retinopathy risk at 5 years on multiple regression analysis (p = 0.037). CONCLUSIONS: Diabetic retinopathy is prevalent in young adults with type 1 diabetes attending specialist secondary care diabetes services. Duration of diabetes was the strongest determinant of retinopathy risk.

Pathophysiological Characteristics Underlying Different Glucose Response Curves: A Latent Class Trajectory Analysis From the Prospective EGIR-RISC Study.

OBJECTIVE: Glucose measurements during an oral glucose tolerance test (OGTT) are useful in predicting diabetes and its complications. However, knowledge of the pathophysiology underlying differences in glucose curve shapes is sparse. We examined the pathophysiological characteristics that create different glucose curve patterns and studied their stability and reproducibility over 3 years of follow-up. RESEARCH DESIGN AND METHODS: We analyzed data from participants without diabetes from the observational cohort from the European Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and Cardiovascular Disease study; participants had a five-time point OGTT at baseline (n = 1,443) and after 3 years (n = 1,045). Measures of insulin sensitivity and secretion were assessed at baseline with a euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance test. Heterogeneous glucose response patterns during the OGTT were identified using latent class trajectory analysis at baseline and at follow-up. Transitions between classes were analyzed with multinomial logistic regression models. RESULTS: We identified four different glucose response patterns, which differed with regard to insulin sensitivity and acute insulin response, obesity, and plasma levels of lipids and inflammatory markers. Some of these associations were confirmed prospectively. Time to glucose peak was driven mainly by insulin sensitivity, whereas glucose peak size was related to both insulin sensitivity and secretion. The glucose patterns identified at follow-up were similar to those at baseline, suggesting that the latent class method is robust. We integrated our classification model into an easy-to-use online application that facilitates the assessment of glucose curve patterns for other studies. CONCLUSIONS: The latent class analysis approach is a pathophysiologically insightful way to classify individuals without diabetes based on their response to glucose during an OGTT.

Pregnancy Exercise and Nutrition With Smartphone Application Support: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of a healthy lifestyle package (an antenatal behavior change intervention supported by smartphone application technology) on the incidence of gestational diabetes mellitus (GDM) in overweight and obese women. METHODS: Women with body mass indexes (BMIs) 25-39.9 were enrolled into this randomized controlled trial. The intervention consisted of specific dietary and exercise advice that addressed behavior change supported by a tailor-designed smartphone application. Women in the control group received usual care. The primary outcome was the incidence of GDM at 28-30 weeks of gestation. To reduce GDM from 15% to 7.2%, we estimated that 506 women would be required to have 80% power to detect this effect size at a significance of .05, that is, 253 in each group. RESULTS: Between March 2013 and February 2016, 565 women were recruited with a mean BMI of 29.3 and mean gestational age of 15.5 weeks. The incidence of GDM did not differ between the two groups, 37 of 241 (15.4%) in the intervention group compared with 36 of 257 (14.1%) in the control group (relative risk 1.1, 95% CI 0.71-1.66, P=.71). CONCLUSIONS: A mobile health-supported behavioral intervention did not decrease the incidence of GDM. CLINICAL TRIAL REGISTRATION: ISRCTN registry, https://www.isrctn.com/, ISRCTN29316280.

Maternal metabolic response to dietary treatment for impaired glucose tolerance and gestational diabetes mellitus.

BACKGROUND: Dietary advice is a standard component of treatment for pregnant women with impaired glucose tolerance (IGT) and gestational diabetes (GDM), yet few studies report glycemic profiles in response to dietary therapies and the optimal dietary approach remains uncertain. AIM: To assess changes in maternal glycemic profile and pregnancy outcomes among women with diet-controlled IGT and GDM. METHODS: Pregnant women who had one or more elevated values on a 3-h oral glucose tolerance test were enrolled. All participants received dietary advice and glucose monitoring as part of routine clinical care. Fasting and 1-h post-prandial blood samples, collected prior to initiation of clinical treatment and repeated 4-6 weeks later, were analyzed for glucose, insulin, and C-peptide. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Women who required pharmacological therapy for glucose control were excluded from analyses. RESULTS: Participants (N = 93) were of moderately older age (mean 33 years), with a high rate of overweight/obesity (mean body mass index (BMI) = 28.65 kg/m2), and were diagnosed late in gestation (mean 29 weeks). Fasting (mean ± SD 4.82 ± 0.53 to 4.60 ± 0.42 mmol/l; p < 0.001) and post-prandial glucose (7.01 ± 1.19 to 6.47 ± 1.10; p = 0.004) decreased significantly following the intervention. Baseline HOMA-IR was elevated (3.12 ± 1.03) but did not significantly decrease (2.78 ± 1.52; p = 0.066). There were high rates of macrosomia (24.7%) and cesarean delivery (32.3%). CONCLUSIONS: Although improvements in blood glucose levels were observed among women with diet-controlled IGT and GDM, this was insufficient to significantly affect insulin resistance or perinatal outcome. Late diagnosis and treatment of IGT/GDM may have contributed to such outcomes.

The relationship between bone turnover and insulin sensitivity and secretion: Cross-sectional and prospective data from the RISC cohort study.

Bone metabolism appears to influence insulin secretion and sensitivity, and insulin promotes bone formation in animals, but similar evidence in humans is limited. The objectives of this study are to explore if bone turnover markers were associated with insulin secretion and sensitivity and to determine if bone turnover markers predict changes in insulin secretion and sensitivity. The study population encompassed 576 non-diabetic adult men with normal glucose tolerance (NGT; n=503) or impaired glucose regulation (IGR; n=73). Baseline markers of bone resorption (CTX) and formation (P1NP) were determined in the fasting state and after a 2-h hyperinsulinaemic, euglycaemic clamp. An intravenous glucose tolerance test (IVGTT) and a 2-h oral glucose tolerance test (OGTT) were performed at baseline, and the OGTT was repeated after 3years. There were no differences in bone turnover marker levels between NGT and IGR. CTX and P1NP levels decreased by 8.0% (p<0.001) and 1.9% (p<0.01) between baseline and steady-state during the clamp. Fasting plasma glucose was inversely associated with CTX and P1NP both before and after adjustment for recruitment centre, age, BMI, smoking and physical activity. However, baseline bone turnover markers were neither associated with insulin sensitivity (assessed using hyperinsulinaemic euglycaemic clamp and OGTT) nor with insulin secretion capacity (based on IVGTT and OGTT) at baseline or at follow-up. Although inverse associations between fasting glucose and markers of bone turnover were identified, this study cannot support an association between insulin secretion and sensitivity in healthy, non-diabetic men.

Lixisenatide as add-on treatment among patients with different ß-cell function levels as assessed by HOMA-ß index.

BACKGROUND: The effect of lixisenatide-a prandial once-daily glucagon-like peptide-1 receptor agonist-on glycaemic control in patients with inadequately controlled type 2 diabetes mellitus (T2DM), stratified by baseline ß-cell function, was assessed. METHODS: The 24-week GetGoal-M, -P and -S trials evaluated the efficacy and safety of lixisenatide in combination with oral antidiabetic agents. This post hoc analysis used data from patients receiving lixisenatide in these trials, divided into matched cohorts by propensity scoring, and stratified according to baseline homeostasis model assessment of ß-cell function (HOMA-ß) index levels, high HOMA-ß: > median HOMA-ß (28.49%); low HOMA-ß: ≤ median. RESULTS: The matched "low" and "high" HOMA-ß index cohorts (N = 546 patients) had comparable baseline parameters. Mean change from baseline in glycated haemoglobin (HbA1c ) was -0.85% and -0.94% for low and high HOMA-ß cohorts, respectively (P = .2607). Reductions from baseline in fasting plasma glucose (FPG; -0.77 vs -1.04 mmol/L; P = .1496) and postprandial plasma glucose (PPG; -5.82 vs -5.61 mmol/L; P = .7511) were similar in the low versus high HOMA-ß index cohorts. Reduction in body weight was significantly greater in the low versus high HOMA-ß index cohort (-2.06 vs -1.13 kg, respectively; P = .0006). CONCLUSIONS: In patients with T2DM, lixisenatide was associated with reduction in HbA1c and improvements in both FPG and PPG, regardless of ß-cell function, indicating that lixisenatide is effective in reducing hyperglycaemia, even in patients with more advanced stages of T2DM and poor residual ß-cell function.

Modification and Validation of the Triglyceride-to-HDL Cholesterol Ratio as a Surrogate of Insulin Sensitivity in White Juveniles and Adults without Diabetes Mellitus: The Single Point Insulin Sensitivity Estimator (SPISE).

BACKGROUND: The triglyceride-to-HDL cholesterol (TG/HDL-C) ratio was introduced as a tool to estimate insulin resistance, because circulating lipid measurements are available in routine settings. Insulin, C-peptide, and free fatty acids are components of other insulin-sensitivity indices but their measurement is expensive. Easier and more affordable tools are of interest for both pediatric and adult patients. METHODS: Study participants from the Relationship Between Insulin Sensitivity and Cardiovascular Disease [43.9 (8.3) years, n = 1260] as well as the Beta-Cell Function in Juvenile Diabetes and Obesity study cohorts [15 (1.9) years, n = 29] underwent oral-glucose-tolerance tests and euglycemic clamp tests for estimation of whole-body insulin sensitivity and calculation of insulin sensitivity indices. To refine the TG/HDL ratio, mathematical modeling was applied including body mass index (BMI), fasting TG, and HDL cholesterol and compared to the clamp-derived M-value as an estimate of insulin sensitivity. Each modeling result was scored by identifying insulin resistance and correlation coefficient. The Single Point Insulin Sensitivity Estimator (SPISE) was compared to traditional insulin sensitivity indices using area under the ROC curve (aROC) analysis and χ(2) test. RESULTS: The novel formula for SPISE was computed as follows: SPISE = 600 × HDL-C(0.185)/(TG(0.2) × BMI(1.338)), with fasting HDL-C (mg/dL), fasting TG concentrations (mg/dL), and BMI (kg/m(2)). A cutoff value of 6.61 corresponds to an M-value smaller than 4.7 mg · kg(-1) · min(-1) (aROC, M:0.797). SPISE showed a significantly better aROC than the TG/HDL-C ratio. SPISE aROC was comparable to the Matsuda ISI (insulin sensitivity index) and equal to the QUICKI (quantitative insulin sensitivity check index) and HOMA-IR (homeostasis model assessment-insulin resistance) when calculated with M-values. CONCLUSIONS: The SPISE seems well suited to surrogate whole-body insulin sensitivity from inexpensive fasting single-point blood draw and BMI in white adolescents and adults.

Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes.

BACKGROUND: Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14-16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Although causality cannot be inferred from association studies, patients in whom the primary cause of insulin resistance can be genetically defined offer unique opportunities to address this challenge. METHODS: We compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR gene) mutations with healthy controls. RESULTS: The absence of significant differences in triacylglycerol species in the INSR group suggest that changes previously observed in epidemiological studies are not purely a consequence of insulin resistance. The presence of triacylglycerols with lower carbon numbers and high saturation in patients with lipodystrophy suggests that these metabolite changes may be associated with primary adipose tissue dysfunction. The observed pattern of triacylglycerol species is indicative of increased de novo lipogenesis in the liver. To test this we investigated the distribution of these triacylglycerols in lipoprotein fractions using size exclusion chromatography prior to mass spectrometry. This associated these triacylglycerols with very low-density lipoprotein particles, and hence release of triacylglycerols into the blood from the liver. To test further the hepatic origin of these triacylglycerols we induced de novo lipogenesis in the mouse, comparing ob/ob and wild-type mice on a chow or high fat diet, confirming that de novo lipogenesis induced an increase in relatively shorter, more saturated fatty acids. CONCLUSIONS: Overall, these studies highlight hepatic de novo lipogenesis in the pathogenesis of metabolic dyslipidaemia in states where energy intake exceeds the capacity of adipose tissue.

Impact of probiotics in women with gestational diabetes mellitus on metabolic health: a randomized controlled trial.

OBJECTIVE: Probiotics are live microorganisms that may confer health benefits on the host. Recent trials of probiotic use among healthy pregnant women demonstrate potential for improved glycemic control. The aim of this study was to investigate the effects of a probiotic capsule intervention on maternal metabolic parameters and pregnancy outcome among women with gestational diabetes. STUDY DESIGN: This double-blind placebo-controlled randomized trial recruited pregnant women with a new diagnosis of gestational diabetes or impaired glucose tolerance following a 3-hour 100-g glucose tolerance test. Women were randomized to a daily probiotic (Lactobacillus salivarius UCC118) or placebo capsule from diagnosis until delivery. Fasting blood samples were collected at baseline and 4-6 weeks after capsule commencement for analysis of glucose, insulin, c-peptide, and lipids. The primary outcome was difference in fasting glucose postintervention, first analyzed on an intention-to-treat basis and followed by per-protocol analysis that excluded women commenced on pharmacological therapy (insulin or metformin). Secondary outcomes were changes in insulin, c-peptide, homeostasis model assessment and lipids, requirement for pharmacological therapy, and neonatal anthropometry. RESULTS: Of 149 women recruited and randomized, there were no differences between the probiotic and placebo groups in postintervention fasting glucose (4.65 ± 0.49 vs 4.65 ± 0.53 mmol/L; P = 373), requirement for pharmacological therapy (17% vs 14%; P = .643), or birthweight (3.57 ± 0.64 vs 3.60 ± 0.57 kg; P = .845). Among 100 women managed with diet and exercise alone, fasting plasma glucose decreased significantly within both the probiotic (4.76 ± 0.45 to 4.57 ± 0.42 mmol/L; P < .001) and placebo (4.85 ± 0.58 to 4.58 ± 0.45 mmol/L; P < .001) groups, but the levels between groups did not differ (P = .316). The late gestation-related rise in total and low-density lipoprotein (LDL) cholesterol was attenuated in the probiotic vs the placebo group (+0.27 ± 0.48 vs +0.50 ± 0.52 mmol/L total cholesterol, P = .031; +0.08 ± 0.51 vs +0.31 ± 0.45 mmol/L LDL cholesterol, P = .011). No differences were noted between groups in other metabolic parameters or pregnancy outcome. CONCLUSION: A probiotic capsule intervention among women with abnormal glucose tolerance had no impact on glycemic control. The observed attenuation of the normal pregnancy-induced rise in total and LDL cholesterol following probiotic treatment requires further investigation, particularly in this obstetric group at risk of future metabolic syndrome.