Maternal lipids are associated with newborn adiposity, independent of GDM status, obesity and insulin resistance: a prospective observational cohort study.

OBJECTIVE: To determine the association between maternal lipaemia and neonatal anthropometrics in Malaysian mother-offspring pairs. DESIGN: Prospective observational cohort study. SETTING: Single tertiary multidisciplinary antenatal clinic in Malaysia. POPULATION: A total of 507 mothers: 145 with gestational diabetes mellitus (GDM); 94 who were obese with normal glucose tolerance (NGT) (pre-gravid body mass index, BMI ≥ 27.5 kg/m2 ), and 268 who were not obese with NGT. METHODS: Maternal demographic, anthropometric, and clinical data were collected during an interview/examination using a structured questionnaire. Blood was drawn for insulin, C-peptide, triglyceride (Tg), and non-esterified fatty acid (NEFA) during the 75-g 2-hour oral glucose tolerance test (OGTT) screening, and again at 36 weeks of gestation. At birth, neonatal anthropometrics were assessed and data such as gestational weight gain (GWG) were extracted from the records. MAIN OUTCOME MEASURES: Macrosomia, large-for-gestational-age (LGA) status, cohort-specific birthweight (BW), neonatal fat mass (NFM), and sum of skinfold thickness (SSFT) > 90th centile. RESULTS: Fasting Tg > 95th centile (3.6 mmol/L) at screening for OGTT was independently associated with LGA (adjusted odds ratio, aOR 10.82, 95% CI 1.26-93.37) after adjustment for maternal glucose, pre-gravid BMI, and insulin sensitivity. Fasting glucose was independently associated with a birthweight ratio (BWR) of >90th centile (aOR 2.06, 95% CI 1.17-3.64), but not with LGA status, in this well-treated GDM cohort with pre-delivery HbA1c of 5.27%. In all, 45% of mothers had a pre-gravid BMI of <23 kg/m2 and 61% had a pre-gravid BMI of ≤ 25 kg/m2 , yet a GWG of >10 kg was associated with a 4.25-fold risk (95% CI 1.71-10.53) of BWR > 90th centile. CONCLUSION: Maternal lipaemia and GWG at a low threshold (>10 kg) adversely impact neonatal adiposity in Asian offspring, independent of glucose, insulin resistance and pre-gravid BMI. These may therefore be important modifiable metabolic targets in pregnancy. TWEETABLE ABSTRACT: Maternal lipids are associated with adiposity in Asian babies independently of pre-gravid BMI, GDM status, and insulin resistance.

Acute Intermittent Porphyria: A rare cause of hyponatraemia.

INTRODUCTION: Hyponatraemia is one of the most frequent laboratory findings in hospitalised patients. We present an unusual case of hyponatraemia in a 23-year-old female secondary to acute intermittent porphyria (AIP), a rare inborn error of metabolism. CASE REPORT: The patient presented with upper respiratory tract infection, fever, seizures and abdominal pain. An initial diagnosis of encephalitis was made. In view of the unexplained abdominal pain with other clinical findings such as posterior reversible encephalopathy syndrome by CT brain, temporary blindness as well as hyponatraemia, acute intermittent porphyria was suspected. Urine delta aminolaevulinic acid (δ-ALA) and porphobilinogen were elevated confirming the diagnosis of AIP. Genetic studies were done for this patient. The patient had a complete resolution of her symptoms with carbohydrate loading and high caloric diet. CONCLUSION: Although rare, AIP should be considered as a cause of hyponatraemia in a patient who presents with signs and/or symptoms that are characteristic of this disease.

Continuous glucose monitoring results in lower HbA1c in Malaysian women with insulin-treated gestational diabetes: a randomized controlled trial.

AIMS: To determine if therapeutic, retrospective continuous glucose monitoring (CGM) improves HbA1c with less hypoglycaemia in women with insulin-treated gestational diabetes mellitus (GDM). METHODS: This prospective, randomized controlled, open-label trial evaluated 50 women with insulin-treated GDM randomized to either retrospective CGM (6-day sensor) at 28, 32 and 36 weeks' gestation (Group 1, CGM, n = 25) or usual antenatal care without CGM (Group 2, control, n = 25). All women performed seven-point capillary blood glucose (CBG) profiles at least 3 days per week and recorded hypoglycaemic events (symptomatic and asymptomatic CBG < 3.5 mmol/l; non-fasting < 4.0 mmol/l). HbA1c was measured at 28, 33 and 37 weeks. In Group 1, both CGM and CBG data were used to manage diabetes, whereas mothers in Group 2 were managed based on CBG data alone. RESULTS: Baseline characteristics (age, pre-pregnancy BMI, HbA1c , total insulin dose) were similar between groups. There was a lower increase in HbA1c from 28 to 37 weeks' gestation in the CGM group [∆HbA1c : CGM + 1 mmol/mol (0.09%), control + 3mmol/mol (0.30%); P = 0.024]. Mean HbA1c remained unchanged throughout the trial in the CGM group, but increased significantly in controls as pregnancy advanced. Mean HbA1c in the CGM group was lower at 37 weeks compared with controls [33 ± 4 mmol/mol (5.2 ± 0.4%) vs. 38 ± 7 mmol/mol (5.6 ± 0.6%), P < 0.006]. Some 92% of the CGM group achieved an HbA1c ≤ 39 mmol/mol (≤ 5.8%) at 37 weeks compared with 68% of the control group (P = 0.012). Neither group experienced severe hypoglycaemia. CONCLUSION: CGM use may be beneficial in insulin-treated GDM because it improves HbA1c compared with usual antenatal care without increasing severe hypoglycaemia. (Clinical Trials Registry No.: NCT02204657).

Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: current evidence and challenges for clinical implementation.

The clinical response to sulphonylurea, an oral antidiabetic agent often used in combination with metformin to control blood glucose in type 2 diabetes (T2DM) patients, has been widely associated with a number of gene polymorphisms, particularly those involved in insulin release. We have reviewed the genetic markers of CYP2C9, ABCC8, KCNJ11, TCF7L2 (transcription factor 7-like 2), IRS-1 (insulin receptor substrate-1), CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP (nitric oxide synthase 1 adaptor protein) genes that predict treatment outcomes of sulphonylurea therapy. A convincing pattern for poor sulphonylurea response was observed in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, limitations in evaluating the available studies including dissimilarities in study design, definitions of clinical end points, sample sizes and types and doses of sulphonylureas used as well as ethnic variability make the clinical applications challenging. Future studies need to address these limitations to develop personalized sulphonylurea medicine for T2DM management.

Relationship between ultrasonographic nerve morphology and severity of diabetic sensorimotor polyneuropathy.

BACKGROUND AND PURPOSE: In the current study, the aim was to characterize the nerve ultrasound cross-sectional areas (CSAs) of type 2 diabetic patients with diabetic sensorimotor polyneuropathy (DSP) of different severities. METHODS: A hundred symptomatic DSP patients and 40 age-matched healthy controls were prospectively recruited. DSP severity was ascertained through the Toronto Clinical Scoring System (TCCS). Nerve electrophysiology and ultrasound were performed on both lower limbs and the non-dominant upper limb. RESULTS: The sural nerve was inexcitable in 19.1% of mild, 40.0% of moderate and 69.0% of severe DSP groups. In contrast, CSAs were measurable in all nerves of DSP patients and were significantly larger compared to controls. Patients with severe DSP had significantly larger ulnar, peroneal, tibial and sural nerves compared to mild DSP patients. By receiver operating characteristic curve analysis, the cut-off value for the sural nerve at 2 mm(2) was a good discriminator (area under the curve 0.88) between the presence and absence of DSP (sensitivity 0.90; specificity 0.74) but performed less well in discriminating between the severity of DSP (cut-off 2.75 mm(2); area under the curve 0.62; sensitivity 0.59; specificity 0.73). Significant correlations were demonstrated between TCSS scores, most neurophysiology parameters and CSAs of the ulnar, peroneal, tibial and sural nerves. CONCLUSION: Nerve ultrasound in DSP reveals enlarged CSAs and these changes worsen with increasing disease severity, thus serving as a useful diagnostic tool especially when neurophysiology is unrevealing.

Hypopituitarism in a Dengue Shock Syndrome Survivor without known Pituitary Adenoma.

Dengue infection is endemic in South East Asia and parts of the Americas. Dengue hemorrhagic fever is characterized by vascular permeability, coagulation-disorders and thrombocytopenia, which can culminate in hypotension i.e. dengue shock syndrome. Hypopituitarism arising as a complication of dengue is extremely rare. Hemorrhagic pituitary apoplexy of pre-existing pituitary adenomas has been rarely reported in dengue. We describe an uncommon case of hypopituitarism in a dengue shock syndrome survivor without known pituitary adenoma. A 49 years old nulliparous lady (from Kuala Lumpur, Malaysia) presented with typical symptoms of hypocortisolism. Postural hypotension was evident with normal secondary sexual characteristics. Further history revealed that she survived an episode of dengue shock syndrome 6 years ago where premature menopause developed immediately after discharge, and subsequently insidious onset of multiple hormonal deficiencies indicative of panhypopituitarism. There were no neuro-ophthalmological symptoms suggestive of pituitary apoplexy during hospitalization for severe dengue. Magnetic resonance imaging of the pituitary 6 years later revealed an empty sella. Autoimmune screen and anti-thyroid peroxidase antibodies were negative. We describe a rare possible causative association of severe dengue with panhypopituitarism without known pituitary adenoma, postulating pituitary infarction secondary to hypotension (mimicking Sheehan's syndrome), or a direct viral cytopathic effect. Subclinical pituitary apoplexy secondary to asymptomatic pituitary hemorrhage however cannot be excluded. Future research is required to determine the need for and timing of pituitary axis assessment among dengue shock syndrome survivors.

Hypopituitarism in a Dengue Shock Syndrome Survivor without known Pituitary Adenoma

Dengue infection is endemic in South East Asia and parts of the Americas. Dengue hemorrhagic fever is characterized by vascular permeability, coagulation-disorders and thrombocytopenia, which can culminate in hypotension i.e. dengue shock syndrome. Hypopituitarism arising as a complication of dengue is extremely rare. Hemorrhagic pituitary apoplexy of pre-existing pituitary adenomas has been rarely reported in dengue. We describe an uncommon case of hypopituitarism in a dengue shock syndrome survivor without known pituitary adenoma. A 49 years old nulliparous lady (from Kuala Lumpur, Malaysia) presented with typical symptoms of hypocortisolism. Postural hypotension was evident with normal secondary sexual characteristics. Further history revealed that she survived an episode of dengue shock syndrome 6 years ago where premature menopause developed immediately after discharge, and subsequently insidious onset of multiple hormonal deficiencies indicative of panhypopituitarism. There were no neuro-ophthalmological symptoms suggestive of pituitary apoplexy during hospitalization for severe dengue. Magnetic resonance imaging of the pituitary 6 years later revealed an empty sella. Autoimmune screen and anti-thyroid peroxidase antibodies were negative. We describe a rare possible causative association of severe dengue with panhypopituitarism without known pituitary adenoma, postulating pituitary infarction secondary to hypotension (mimicking Sheehan’s syndrome), or a direct viral cytopathic effect. Subclinical pituitary apoplexy secondary to asymptomatic pituitary hemorrhage however cannot be excluded. Future research is required to determine the need for and timing of pituitary axis assessment among dengue shock syndrome survivors.

Hypothalamic pituitary dysfunction amongst nasopharyngeal cancer survivors.

PURPOSE: Radiation fields for nasopharyngeal cancer (NPC) include the base of skull, which places the hypothalamus and pituitary at risk of damage. We aimed to establish the prevalence, pattern and severity of hypothalamic pituitary (HP) dysfunction amongst NPC survivors. METHODS: We studied 50 patients (31 males) with mean age 57 ± 12.2 years who had treatment for NPC between 3 and 21 years (median 8 years) without pre-existing HP disorder from other causes. All patients had a baseline cortisol, fT4, TSH, LH, FSH, oestradiol/testosterone, prolactin and renal function. All patients underwent dynamic testing with insulin tolerance test to assess the somatotroph and corticotroph axes. Baseline blood measurements were used to assess thyrotroph, gonadotroph and lactotroph function. RESULTS: Hypopituitarism was present in 82% of patients, 30% single axis, 28% two axes, 18% three axes and 6% four axes deficiencies. Somatotroph deficiency was most common (78%) while corticotroph, gonadotroph and thyrotroph deficiencies were noted in 40% (4 complete/16 partial), 22 and 4% of the patients respectively. Hyperprolactinaemia was present in 30% of patients. The development of HP dysfunction was significantly associated with the time elapsed from irradiation, OR 2.5 (1.2, 5.3), p = 0.02, for every 2 years post treatment. The use of concurrent chemo-irradiation (CCRT) compared to those who had radiotherapy alone was also significantly associated with HP dysfunction, OR 14.5 (2.4, 87.7), p < 0.01. CONCLUSION: Despite low awareness and detection rates, HP dysfunction post-NPC irradiation is common. Use of CCRT may augment time related pituitary damage. As these endocrinopathies result in significant morbidity and mortality we recommend periodic assessment of pituitary function amongst NPC survivors.

Causes of Low HbA1c in Malaysian University Hospital.

INTRODUCTION: Glycohemoglobin (HbA1c) most accurately reflects the previous two to three months of glycaemic control. HbA1c should be measured regularly in all patients with diabetes, and values should be maintained below 7% to prevent the risk of chronic complications. Apart from the genetic variants of haemoglobins many other conditions also known to affect HbA1c measurements. In this study we evaluated the conditions that cause low HbA1c results. METHODS AND MATERIALS: The data was collected retrospectively HbA1c was measured in our laboratory by Biorad Variant II turbo 2.0. The method is based on chromatographic separation of HbA1c on a cation exchange cartridge. This method has been certified by National Glycohemoglobin Standardization Programme (NGSP). 58437 requests were received in a period of one year (January to December 2011). Medical records were reviewed to identify the conditions that might be associated with these low values. RESULTS: Among 58437 samples analysed, 53 patients had HbA1c levels < 4.0%. Fourteen patients had haemoglobinopathy. In 34 patients without Hb variants had conditions such as chronic liver disease, chronic kidney disease, haemolytic anaemia, pregnancy, and anaemia of chronic disease. Five non-pregnant individuals who were screened for diabetes mellitus had HbA1c levels < 4%. CONCLUSION: Our study underscores the importance of that both laboratories and the physicians should be aware of the factors that can influence the HbA1c results. The haematological status should be taken into consideration for proper interpretation of HbA1c results.

Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision.

BACKGROUND: The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. OBJECTIVE: To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. SUBJECTS AND METHODS: FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. RESULTS: Si was lower in insulinoma patients before, compared with after surgery (3.37 +/- 0.62 vs. 6.24 +/- 1.09 SE [x10(-4)] min(-1)microU(-1) ml, P < 0.05). Sg was similar in patients pre- and post-surgery (3.0 +/- 0.67 vs. 2.4 +/- 0.6 [x10(-2)] min(-1), NS). CONCLUSIONS: Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.