Early pregnancy metabolic syndrome and risk for adverse pregnancy outcomes: findings from Rajarata Pregnancy Cohort (RaPCo) in Sri Lanka.

BACKGROUND: Despite the intergenerational effects of metabolic disorders, evidence is greatly lacking on early pregnancy metabolic syndrome (MetS) and its effects on pregnancy outcomes from low- and middle-income countries. Thus, this prospective cohort of South Asian pregnant women aimed to evaluate how early pregnancy MetS would affect pregnancy outcomes. METHODS: A prospective cohort study was conducted among first-trimester (T1) pregnant women of Anuradhapura district, Sri Lanka recruited to the Rajarata Pregnancy Cohort in 2019. MetS was diagnosed by the Joint Interim Statement criteria before 13 weeks of gestational age (GA). Participants were followed up until their delivery, and the major outcomes measured were large for gestational age (LGA), small for gestational age (SGA), preterm birth (PTB) and miscarriage (MC). Gestational weight gain, gestational age at delivery and neonatal birth weight were used as measurements to define the outcomes. Additionally, outcome measures were re-assessed with adjusting fasting plasma glucose (FPG) thresholds of MetS to be compatible with hyperglycemia in pregnancy (Revised MetS). RESULTS: 2326 T1 pregnant women with a mean age of 28.1 years (SD-5.4), and a median GA of 8.0 weeks (IQR-2) were included. Baseline MetS prevalence was 5.9% (n = 137, 95%CI-5.0-6.9). Only 2027 (87.1%) women from baseline, had a live singleton birth, while 221(9.5%) had MC and 14(0.6%) had other pregnancy losses. Additionally, 64(2.8%) were lost to follow-up. A higher cumulative incidence of LGA, PTB, and MC was noted among the T1-MetS women. T1-MetS carried significant risk (RR-2.59, 95%CI-1.65-3.93) for LGA, but reduced the risk for SGA (RR-0.41, 95%CI-0.29-0.78). Revised MetS moderately increased the risk for PTB (RR-1.54, 95%CI-1.04-2.21). T1-MetS was not associated (p = 0.48) with MC. Lowered FPG thresholds were significantly associated with risk for all major pregnancy outcomes. After adjusting for sociodemographic and anthropometric confounders, revised MetS remained the only significant risk predictor for LGA. CONCLUSION: Pregnant women with T1 MetS in this population are at an increased risk for LGA and PTB and a reduced risk for SGA. We observed that a revised MetS definition with lower threshold for FPG compatible with GDM would provide a better estimation of MetS in pregnancy in relation to predicting LGA.

Comparison of global definitions of metabolic syndrome in early pregnancy among the Rajarata Pregnancy Cohort participants in Sri Lanka.

Metabolic syndrome (MetS) in pregnancy shows epigenetic associations with intergenerational inheritance of metabolic diseases. The presence of different diagnostic criteria influences MetS prevalence estimates. We evaluated MetS and metabolic derangements to determine the utility of its assessment in early pregnancy. A cross-sectional analysis of metabolic derangements in pregnant women with period of gestation (POG) ≤ 12 weeks was done among Rajarata Pregnancy Cohort participants in Sri Lanka. 2682 women with mean age 27.9 year (SD-5.5) and median POG 8.0wk (IQR-3) were analyzed. Mean levels of triglycerides (TG), total cholesterol (TC), high-density-lipoprotein (HDL), low-density-lipoprotein (LDL), fasting plasma glucose, and 2 h oral glucose tolerance test were 87.71 (SD 38.7), 172.2 (SD 34.7), 49.6 (SD 11.5), 122.6 (SD 32.3), 82.2 (SD 12.8) and 120.3 (SD 11.5) respectively. All serum lipids except LDL increase significantly from 6 to 12 weeks, with TG by 23 and TC by 8 units. High MetS prevalence was observed with AHA/NHLBI (n = 150, 5.6%, 95% CI 4.8-6.5) followed by IDF (n = 144, 5.4%, 95% CI 4.6-6.3), NCEP-ATP III (n = 112, 4.2%, 95% CI 3.4-5.0) and WHO (n = 81, 3.0%, 95% CI 2.4-3.7) definitions respectively. Significant difference in prevalence was noted among different sociodemographic characteristics (p < 0.001). Regardless of the criterion used, the change of metabolic parameters in early pregnancy leads to significant differences in prevalence estimates of MetS. The best MetS definition concerning pregnancy outcomes needs to be determined with prospective studies.

Does intensive glycaemic control promote healing in diabetic foot ulcers? - a feasibility study.

INTRODUCTION: One in four diabetes patients will develop a foot ulcer over their lifetime. The role of glycaemic control in the healing of foot ulcers in diabetes patients is not supported by randomised controlled trial (RCT) data. OBJECTIVES: To determine the feasibility of an RCT of glycaemic control with intensive insulin therapy in diabetic foot ulcer, by assessing: entry criteria, fasting capillary blood glucose (FCBG) medication satisfaction and sensitivity of different ulcer-healing endpoints to glycaemic control. DESIGN: Two substudies: one cross-sectional and one single-arm prospective. SETTING: Single-centre secondary care diabetic foot clinic in New Zealand. PARTICIPANTS: Substudy 1: 78 participants consisting of all people ≥18 years with a diabetic foot ulcer presenting to the clinic over 35 weeks in 2015.Substudy 2: 15 participants from Substudy 1 consenting to intensive insulin therapy. INTERVENTION: Substudy 1: None.Substudy 2: Intensive insulin therapy with standard podiatry care over 24 weeks. OUTCOME: Substudy 1: Proportion of participants satisfying potential RCT entry criteria; medication satisfaction (Diabetes Medication Satisfaction).Substudy 2: FCBG, index ulcer healing time, index ulcer size, health-related quality of life (HRQoL; EuroQol 5 Dimensions 5 Levels and Diabetic Foot Ulcer Scale-Short Form). RESULTS: Proportion in Substudy 1 satisfying all entry criteria was 31% (95% CI 21 to 42). FCBG values decreased between baseline and study end (difference -3.7 mmol/L, 95% CI -6.5 to -0.8); 83% (95% CI 44 to 95) of ulcers healed by 24 weeks. FCBG correlated negatively with medication satisfaction. Ulcer area logarithm was most sensitive to FCBG changes, displaying significant negative correlation with HRQoL outcomes. Detecting a 30% between-group difference in this outcome (80% power, α=5%) requires 220 participants per arm, achievable within 1 year with 15 centres similar to study setting. CONCLUSIONS: An adequately powered RCT requires cooperation between a large number of centres. Ulcer area logarithm should be primary endpoint. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12617001414303.

Pharmacokinetics of metformin in patients with chronic kidney disease stage 4 and metformin-naïve type 2 diabetes.

The pharmacokinetics of metformin therapy in patients with chronic kidney disease stage 4 (CKD-4) were studied using data from the largest Phase I consecutive cohort trial yet performed in this population. Eighteen metformin-naïve men and women with Type 2 Diabetes and creatinine clearance (CrCl) in the range 18-49 mL/min (eGFR 15-29 mL/min/1.73 m2) were allocated to daily immediate-release metformin of 250 mg, 500 mg, or 1000 mg. A first-dose profile and trough concentrations for 4 weeks were taken on all patients. Pharmacokinetic (PK) parameters were estimated by fitting a first-order compartment model with absorption in a peripheral compartment to concentrations measured 24 hours post-first dose. Single-dose PK parameters time to maximum concentration (tmax) and maximum concentration (Cmax) were consistent with previous observations in patients with normal renal function (healthy and diabetic), as was the association between CrCl and apparent total oral clearance (Cl/F). However, patients with a CrCl below 32 mL/min had trough concentrations that were consistently above the steady-state minimum implied by the population PK model. This suggests the model may not apply to patients with CrCl below 32 mL/min. Metformin in doses of 500-1000 mg/day could be taken by CKD-4 patients. However, the single-compartment model breaks down as CrCl declines below 32 mL/min suggesting that metformin levels should be monitored regularly in progressive stage 4 CKD.

Insulinoma and Tuberous Sclerosis: A Possible Mechanistic Target of Rapamycin (mTOR) Pathway Abnormality?

A 23-year-old New Zealand Maori male with tuberous sclerosis (TSC) and associated neurocognitive abnormalities presented with altered behavior and increasing seizure frequency. Endogenous hyperinsulinemia from an underlying insulinoma was confirmed and this was managed surgically. This case represents only the sixth description of insulinoma in TSC to date. The role of the hamartin-tuberin complex in regulation of the mechanistic target of rapamycin pathway provides a plausible pathogenetic mechanism between insulinoma and TSC. This rare disease association should be considered in TSC patients who present with otherwise unexplained worsening neurocognitive symptoms.

Pedobarography as a clinical tool in the management of diabetic feet in New Zealand: a feasibility study.

BACKGROUND: The peripheral complications of diabetes mellitus remain a significant risk to lower-limb morbidity. In New Zealand, risk of diabetes, comorbidity and lower-limb amputation are highly-differential between demographic groups, particularly ethnicity. There is growing and convincing evidence that the use of pedobarography - or plantar pressure measurement - can usefully inform diabetic foot care, particularly with respect to the prevention of re-ulceration among high-risk patients. METHODS: For the current feasibility study, we embedded pedobarographic measurements into three unique diabetic foot clinic settings in the New Zealand context, and collected pedobarographic data from n = 38 patients with diabetes using a platform-based (Novel Emed) and/or in-shoe-based system (Novel Pedar). Our aim was to assess the feasibility of incorporating pedobarographic testing into the clinical care of diabetic feet in New Zealand. RESULTS AND CONCLUSIONS: We observed a high response rate and positive self-reported experience from participants. As part of our engagement with participants, we observed a high degree of lower-limb morbidity, including current ulceration and chronic foot deformities. The median time for pedobarographic testing (including study introduction and consenting) was 25 min. Despite working with a high-risk population, there were no adverse events in this study. In terms of application of pedobarography as a clinical tool in the New Zealand context, the current feasibility study leads us to believe that there are two avenues that deserve further investigation: a) the use of pedobarography to inform the design and effectiveness of offloading devices among high-risk diabetic patients; and b) the use of pedobarography as a means to increase offloading footwear and/or orthoses compliance among high-risk diabetic patients. Both of these objectives deserve further examination in New Zealand via clinical trial.

Extending Metformin Use in Diabetic Kidney Disease: A Pharmacokinetic Study in Stage 4 Diabetic Nephropathy.

INTRODUCTION: Metformin use in advanced chronic kidney disease is controversial. This study sought to examine the pharmacokinetics, safety, and efficacy of low-dose metformin in patients with type 2 diabetes and stage 4 chronic kidney disease. METHODS: In this open-label, phase I trial, 3 consecutive cohorts (1, 2, and 3) of 6 patients each were recruited to receive 250-, 500-, or 1000-mg once-daily doses of metformin, respectively. All patients underwent a first-dose pharmacokinetic profile and weekly trough metformin concentrations for the duration of 4 weeks of daily therapy. Prespecified clinical and biochemical safety endpoints of serum bicarbonate, venous pH, and serum lactate were assessed weekly. Efficacy was assessed by pre- and post-HbA1c and 72-hour capillary glucose monitoring. RESULTS: There was no evidence of accumulation of metformin in any cohort. There were no episodes of hyperlactatemia or metabolic acidosis and no significant change in any biochemical safety measures. Median (interquartile range) observed trough concentrations of metformin in cohorts 1, 2, and 3 were 0.083 (0.121) mg/l, 0.239 (0.603) mg/l, and 1.930 (3.110) mg/l, respectively. Average capillary glucose concentrations and mean HbA1c decreased in all cohorts. DISCUSSION: In our patient cohorts with diabetes and stage 4 chronic kidney disease, treatment with 4 weeks of low-dose metformin was not associated with adverse safety outcomes and revealed stable pharmacokinetics. Our study supports the liberalization of metformin use in this population and supports the use of metformin assays for more individualized dosing.

Calciphylaxis - A case study in a patient with Maori heritage.

This case history describes a rare complaint - Calciphylaxis, seen in a New Zealand Maori patient undergoing renal dialysis. This condition causes non-healing tissue ulceration, typically with sepsis and is associated with a very high mortality rate. The need for vigilance among health professionals is highlighted, including the risk factors that may faciliate an early diagnosis; together with the value associated with a multi-disciplinary team approach to management.

Lisfranc fracture-dislocation precipitating acute Charcot arthopathy in a neuropathic diabetic foot: a case report.

The Lisfranc injury is relatively uncommon yet remains popular in the literature due to its variable causative mechanisms and subtleties in radiographic features despite its potential for disabling long term outcomes if treatment is inadequate, inappropriate or delayed. These injuries are especially pertinent in diabetic patients, especially those with neuropathy, since they are more common, can lead to Charcot neuropathic joint, ulcers and have different causative mechanisms compared to the general population. We describe the case of a neuropathic diabetic patient who presented with a Lisfranc injury which precipitated the development of acute Charcot arthropathy in the right foot. The case serves to illustrate several salient points about the Lisfranc joint and related injuries in diabetic patients.

High prevalence of gout in patients with Type 2 diabetes: male sex, renal impairment, and diuretic use are major risk factors.

AIMS: Gout and hyperuricaemia are recognised features of the metabolic syndrome. The objective of this study was to determine the prevalence of gout in patients with diabetes. METHODS: We studied 292 consecutive outpatients attending diabetes clinics between August and September 2005. A self-reported history of gout was obtained, and was confirmed by clinical chart review. Information regarding associated comorbidities was also recorded. Current treatments were compared with published EULAR guidelines for the management of gout. RESULTS: Gout was confirmed in 0/27 (0%) patients with Type 1 diabetes and 59/265 (22%) of patients with Type 2 diabetes (p<0.01). Prevalence rates varied depending on age and sex, and were highest (41%) in men with type 2 diabetes over the age of 65 years. Multivariate analysis showed that the following variables were independent predictors for gout in patients with Type 2 diabetes: male sex (adjusted OR 4.4, 95%CI 2.1-9.6), impaired renal function (adjusted OR 1.2 for every 10 ml/min reduction in GFR, 95%CI 1.1-1.4), diuretic use (adjusted OR 3.2, 95%CI 1.6-6.6), and high triglycerides (adjusted OR 2.2, 95%CI 1.0-4.7) Only 28/59 (47%) of patients with gout were on urate-lowering therapy. A further 24/59 (41%) met recommended criteria for urate-lowering therapy but were not receiving this medication. CONCLUSION: This study has demonstrated a high prevalence of gout in patients with Type 2 diabetes. Improved recognition of those at high risk of gout is needed to ensure optimal management of these patients.

Demonstration of a hyperglycemia-driven pathogenic abnormality of copper homeostasis in diabetes and its reversibility by selective chelation: quantitative comparisons between the biology of copper and eight other nutritionally essential elements in normal and diabetic individuals.

We recently showed that treatment with the Cu(II)-selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu]serum and HbA1c. Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic Cu(II). We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic Cu(II).

Three-dimensional assessment of left ventricular systolic strain in patients with type 2 diabetes mellitus, diastolic dysfunction, and normal ejection fraction.

Left ventricular (LV) diastolic dysfunction often occurs in patients with type 2 diabetes mellitus (DM) independent of atherosclerotic coronary artery disease, myocardial ischemia, and regional wall motion anomalies. Limited information exists on LV myocardial tissue strain in this patient group. We measured 3-dimensional (3-D) parameters of LV systolic and diastolic functions in 28 patients who had type 2 DM (age 33 to 70 years), standard echocardiographic evidence of LV diastolic dysfunction, and normal LV ejection fraction, and 31 normal control subjects (age 19 to 74 years) who had no evidence of cardiac disease, with multislice cine anatomic and tagged magnetic resonance imaging. Three-dimensional analysis of the resulting images showed that peak systolic mitral valve plane displacement was 12% smaller (p = 0.040) and peak diastolic mitral valve plane velocity was 21% lower (p = 0.008) in patients who had DM than in normal controls. Peak systolic circumferential and longitudinal strains and principal 3-D shortening strain were 14%, 22%, and 10% smaller, respectively, in the DM group (p <0.001 for each). Peak diastolic rate of relaxation of circumferential and longitudinal strains and principal 3-D shortening strain were 35%, 32%, and 33% lower, respectively, in the DM group (p <0.001 for each). Thus, LV systolic circumferential, longitudinal and 3-D principal strains, and diastolic strain rates are impaired in patients who have type 2 DM, LV diastolic dysfunction, and normal LV ejection fraction.

Regeneration of the heart in diabetes by selective copper chelation.

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.