The evolving contribution of non-communicable diseases to maternal mortality in Jamaica, 1998-2015: a population-based study.

OBJECTIVE: To describe trends in indirect cause-specific pregnancy-related mortality from 1998 to 2015. DESIGN: Secondary analysis of annual, national cross-sectional database of maternal and late maternal deaths, identified through active surveillance of deaths among women aged 10-50 years. SETTING: Jamaica, a middle-income Caribbean country. POPULATION: Maternal and late maternal deaths. METHODS: Descriptive trend analyses of demographic and cause-specific maternal and pregnancy-related mortality ratios undertaken comparing the periods 1998-2003, 2004-2009 and 2010-2015. Multivariate logistic regression was used to confirm changes in risk of indirect death. MAIN OUTCOME MEASURES: Maternal, pregnancy-related, direct, indirect and cause-specific mortality ratios (deaths/100 000 live births). RESULTS: Maternal deaths from indirect conditions increased between the first two periods (P = 0.004) and stabilised in the third (P = 0.085). Associated with upward movement in cardiovascular deaths (P[trend] = 0.003), women under 25 years were at elevated risk (odds ratio 1.44, 95% CI 1.00-2.08; P = 0.052). Haematological/immunological conditions (69% sickle cell disease) ranked second but did not vary with time. Health service utilisation was similar across age, parity, health region and major cause categories (non-communicable diseases, non-obstetric infections, direct), however women with indirect conditions spent more time in hospital (median 5 days versus 3 days) and more often died after the puerperium. CONCLUSIONS: Medical conditions, especially cardiovascular disease, are increasingly associated with maternal and late maternal mortality. Middle-income countries need to simultaneously improve management of indirect conditions, while redoubling efforts to reduce direct deaths. Postpuerperal medical services should be integrated into routine infant health services to improve continuity of care during this high-risk period. TWEETABLE ABSTRACT: Maternal survival (SDG 3.1) in LMICs requires better care for women with both non-communicable diseases and obstetric conditions.

Clinical and molecular characterization of a novel PLIN1 frameshift mutation identified in patients with familial partial lipodystrophy.

Perilipin 1 is a lipid droplet coat protein predominantly expressed in adipocytes, where it inhibits basal and facilitates stimulated lipolysis. Loss-of-function mutations in the PLIN1 gene were recently reported in patients with a novel subtype of familial partial lipodystrophy, designated as FPLD4. We now report the identification and characterization of a novel heterozygous frameshift mutation affecting the carboxy-terminus (439fs) of perilipin 1 in two unrelated families. The mutation cosegregated with a similar phenotype including partial lipodystrophy, severe insulin resistance and type 2 diabetes, extreme hypertriglyceridemia, and nonalcoholic fatty liver disease in both families. Poor metabolic control despite maximal medical therapy prompted two patients to undergo bariatric surgery, with remarkably beneficial consequences. Functional studies indicated that expression levels of the mutant protein were lower than wild-type protein, and in stably transfected preadipocytes the mutant protein was associated with smaller lipid droplets. Interestingly, unlike the previously reported 398 and 404 frameshift mutants, this variant binds and stabilizes ABHD5 expression but still fails to inhibit basal lipolysis as effectively as wild-type perilipin 1. Collectively, these findings highlight the physiological need for exquisite regulation of neutral lipid storage within adipocyte lipid droplets, as well as the possible metabolic benefits of bariatric surgery in this serious disease.

Inflammatory and oxidative stress responses to high-carbohydrate and high-fat meals in healthy humans.

The postprandial state is hypothesised to be proinflammatory and prooxidative, but the relative contributions of fat versus carbohydrate are unclear. Therefore, we examined inflammation and oxidative stress responses in serum and skeletal muscle before and after 1000 kcal meals, which were high in either fat or carbohydrate in 15 healthy individuals. Serum and muscle expression of IL6 was elevated 3 hours after each meal, independently of macronutrient composition (P < 0.01). Serum IL18 was decreased after high-fat meal only (P < 0.01). Plasma total antioxidative status and muscle Cu/Zn-superoxide dismutase were decreased after high-carbohydrate meal only (P < 0.05). We conclude that a high-carbohydrate meal may evoke a greater postprandial oxidative stress response, whereas both fat and carbohydrate increased IL6. We speculate that the observed increases in postprandial IL6, without increases in any other markers of inflammation, may indicate a normal IL6 response to enhance glucose uptake, similar to its role postexercise.

Obesity is associated with activated and insulin resistant immune cells.

BACKGROUND: Obesity and type 2 diabetes mellitus are characterized by insulin resistance and 'low-grade inflammation'; however, the pathophysiological link is poorly understood. To determine the relative contribution of obesity and insulin resistance to systemic 'inflammation', this study comprehensively characterized circulating immune cells in different grades of obesity. METHODS: Immune cell phenotypes and activation status were analysed by flow cytometry cross-sectionally in morbidly obese (n = 16, body mass index (BMI) 42.2 ± 5.4 kg/m2), overweight (n = 13, BMI 27.4 ± 1.6 kg/m2) and normal weight (n = 12, BMI 22.5 ± 1.9 kg/m2) subjects. RESULTS: Obese, but not overweight subjects, had increased activation marker expression on neutrophils, monocytes, T-lymphocytes and polarization of T helper cells towards a pro-inflammatory type 1-phenotype (Th1). Th1 numbers correlated positively with the degree of insulin resistance (homeostasis model assessment, p < 0.05). Lymphocytes from obese subjects showed reduced insulin-stimulated AKT-phosphorylation in vitro. Supra-physiological insulin concentrations did not affect T-cell differentiation, which under normal circumstances would promote an anti-inflammatory T helper type 2-phenotype. CONCLUSIONS: These results show that morbid obesity is characterized by circulating immune cells that are activated and insulin resistant, with the T-cell balance polarized towards a pro-inflammatory Th1 phenotype. The loss of insulin-induced suppression of inflammatory phenotypes in circulating immune cells could contribute to the systemic and adipose tissue inflammation found in morbid obesity.

Recreational drug use in type 1 diabetes: an invisible accomplice to poor glycaemic control?

Recreational drug use during 'rave' parties is increasingly popular, but the impact of recreational drug use in type 1 diabetes (T1D) is not known. We determined the self-reported pattern and effects of recreational/illicit drug use in Australians with T1D people by inviting people with T1D to participate in an anonymous online/paper survey of drug use, through national radio broadcast and online/hospital advertising. Of the people with T1D who responded to our survey, more than three quarters reported having used recreational/illicit drug, but few people had informed health professionals about drug use. Drug use was associated with worse glycaemic control and higher risk of diabetic ketoacidosis. Medical awareness of common, currently underreported, drug use in young people with T1D is essential. It offers the possibility of helping such patients improve related suboptimal metabolic control.

Insulin-sensitive obesity in humans - a 'favorable fat' phenotype?

In most humans, obesity and insulin resistance coexist. However, a unique group of obese individuals, who exhibit better insulin sensitivity than expected for their adiposity, has been the focus of recent research interest. We critically examine cross-sectional and lifestyle intervention studies in obese humans classified as 'insulin-sensitive' versus 'insulin-resistant' and review the few longitudinal studies comparing rates of cardiovascular disease, type 2 diabetes and all-cause mortality in these groups of individuals. We suggest that reduced deposition of fat, particularly of bioactive lipid intermediates, in muscle and liver is potentially protective. We propose that dynamic interventional studies in insulin-sensitive obese humans may increase understanding of the metabolic factors that play a role in obesity-associated insulin resistance in humans.

Identification of undiagnosed type 2 diabetes by systolic blood pressure and waist-to-hip ratio.

AIMS/HYPOTHESIS: We estimated the current prevalence of type 2 diabetes in the Vietnamese population and developed simple diagnostic models for identifying individuals at high risk of undiagnosed type 2 diabetes. METHODS: The study was designed as a cross-sectional investigation with 721 men and 1,421 women, who were aged between 30 and 72 years and were randomly sampled from Ho Chi Minh City (formerly Saigon) in Vietnam. A 75 g oral glucose tolerance test to assess fasting and 2 h plasma glucose concentrations were determined for each individual. The ADA diagnostic criteria were used to determine the prevalence of type 2 diabetes. WHR and blood pressure were also measured in all individuals. RESULTS: The prevalence of type 2 diabetes was 10.8% in men and 11.7% in women. Higher WHR and blood pressure were independently associated with a greater risk of type 2 diabetes. Compared with participants without central obesity and hypertension, the odds of diabetes was increased by 6.4-fold (95% CI 3.2-13.0) in men and 4.1-fold (2.2-7.6) in women with central obesity and hypertension. Two nomograms were developed that help identify men and women at high risk of type 2 diabetes. CONCLUSIONS/INTERPRETATION: The current prevalence of type 2 diabetes in the Vietnamese population is high. Simple field measurements such as waist-to-hip ratio and systolic blood pressure can identify individuals at high risk of undiagnosed type 2 diabetes.

Hyperglycaemia in hospital inpatients: still a sticky situation.

BACKGROUND: Diabetes diagnosis is delayed 4-7 years and 50% are undiagnosed. Forty percent of hospitalized patients with any blood glucose level (BGL) > or = 10 mmol/L have diabetes 3 months post-discharge, yet less than 5% are detected in hospital. We review identification of, and responses to, hyperglycaemia in inpatients at a teaching hospital. METHODS: The world's largest retrospective review of medical records for inpatients with venous BGL > or = 11.1 mmol/L without known diabetes over 12 months (2005-2006). The primary outcome was recognition of hyperglycaemia; secondary outcomes were treatment and documentation of follow up. Logistic regression was performed with variables including BGL, admitting team, length of stay and endocrine team review. RESULTS: Of 10 973 people screened, 162 were eligible. The median age was 58 years and BGL 13.3 mmol/L, with increased mortality and length of stay. Hyperglycaemia was noted as definitely in 26%, maybe in 24% and definitely not in 50%. Forty percent of patients were treated in hospital and 19% on discharge. Follow up was documented for 24%. A higher BGL and review by the endocrine team were strongly associated with clinical recognition on uni- and multivariate analyses. However, where an endocrine review was sought for non-hyperglycaemia reasons, similar rates of non-recognition occurred. CONCLUSION: Despite evidence for improved inpatient outcomes when treated, and high short-term progression to frank diabetes, inpatient hyperglycaemia remains frequently missed. In-hospital recognition is cheap, and vital for the implementation of activities to improve outcomes and prevent progression and complications. Changes to systems for checking pathology results, medical officer education and inpatient screening guidelines are indicated.

A family history of type 2 diabetes increases risk factors associated with overfeeding.

AIMS/HYPOTHESIS: The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. METHODS: We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp). RESULTS: Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ individuals having gained significantly more weight than FH- individuals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001). CONCLUSIONS: Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding. TRIAL REGISTRATION: ClinicalTrials.gov NCT00562393 FUNDING: The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).

Challenges in secondary stroke prevention: prevalence of multiple metabolic risk factors, including abnormal glycaemia, in ischaemic stroke and transient ischaemic attack.

BACKGROUND: Secondary prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA) mandates identification and treatment of multiple metabolic risk factors. The aim was to determine the prevalence of abnormal glycaemia, hypertension and dyslipidaemia in patients presenting to an Acute Stroke Unit of a tertiary referral teaching hospital with IS or TIA. METHODS: We reviewed the clinical characteristics of consecutive patients presenting with symptoms of acute stroke or TIA between 1 February 2006 and 30 June 2007 to determine the prevalence of diabetes, impaired fasting glucose (IFG), post-stroke dysglycaemia (PSD), hypertension and dyslipidaemia. RESULTS: Mean age +/- SD of the 224 patients (84 female) was 71 +/- 15 years. Seventy per cent (n= 157) of patients presented with IS and 30% (n= 67) with TIA. Of the cohort, 15% (n= 33) had previously diagnosed diabetes, 10% (n= 22) were diagnosed with diabetes during admission and 19% (n= 42) had IFG diagnosed during admission. A further 4% (n= 9) were classified as having PSD. Sixty-two per cent (n= 139) of patients had previously diagnosed hypertension; another 7% (n= 15) were diagnosed during admission. Eighty-eight per cent (n= 197) of patients had dyslipidaemia. Thirty per cent had all three risk factors concurrently. CONCLUSION: Abnormal glycaemia was present in almost half the patients presenting with IS/TIA, with the majority of cases undiagnosed. One-third of patients had abnormal glycaemia, hypertension and dyslipidaemia concurrently. Patients presenting with stroke should be routinely screened for abnormal glycaemia in concert with other vascular risk factors.

Managing young people with Type 1 diabetes in a 'rave' new world: metabolic complications of substance abuse in Type 1 diabetes.

The taxing transition from adolescence towards adulthood intensifies the impact of a chronic illness such as Type 1 diabetes. It is not uncommon for young people with Type 1 diabetes to use recreational drugs for emotional relief to escape the day-to-day burden of chronic disease. Despite increasing use, especially in the setting of 'rave' parties, there is professional lack of understanding of the impact of recreational drug use on glycaemia and metabolic complications. The current review describes the prevalence of substance abuse in Type 1 diabetes and the acute impact of designer drugs on its management. We propose a practical approach to improve care of young people with Type 1 diabetes using designer drugs.

Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.

BACKGROUND: The aim of this study was to determine whether pre-existing diabetes mellitus increases the risk of rejection, infection and/or death in cystic fibrosis patients undergoing bilateral sequential single-lung transplantation. METHODS: A retrospective audit of 25 consecutive patients with cystic fibrosis who underwent bilateral sequential single-lung transplantation between 1 January 2003 and 31 December 2005 at a tertiary referral hospital was carried out. RESULTS: Although 32% patients had diabetes diagnosed before lung transplantation, 92% had random blood glucose levels > or =11.1 mmol/L requiring insulin during admission. Patients with pre-existing diabetes had increased infection-related (3.9 vs 1.2, P= 0.01) and putative rejection-related (1.4 vs 0.5, P= 0.04) hospital admissions post-transplantation compared with those without diabetes pre-transplant. During the period of observation, four of eight patients with a prior diagnosis of diabetes died compared with none of 17 patients without prior diabetes (P= 0.0055). CONCLUSION: Almost all cystic fibrosis patients develop hyperglycaemia after lung transplantation, but patients with prior diabetes have more complication-related admissions to hospital and a higher mortality rate.

Abnormal postprandial PYY response in insulin sensitive nondiabetic subjects with a strong family history of type 2 diabetes.

OBJECTIVE: Gut-derived hormone peptide YY (PYY) is low in subjects with obesity and type 2 diabetes (T2D). However, it is unknown whether this is a primary defect or a consequence of metabolic disturbances. In this study, we aimed to assess whether low fasting and postprandial PYY secretion is an early defect, potentially promoting the development of obesity and T2D, and whether it is modified by macronutrient content. DESIGN: Prospective cross-sectional cohort study. SUBJECTS: Nine individuals with a strong family history of T2D (REL) and seven age and adiposity matched individuals with no family history of T2D (CON). INTERVENTIONS: Metabolic studies including hyperinsulinemic-euglycemic clamp, dual X-ray absorptiometry and two meal tests containing 1000 kcal with an either high fat (76%) or high carbohydrate (76%) content. MAIN OUTCOME MEASURES: Fasting and postprandial PYY levels were measured and analyzed for potential correlations with markers for adiposity and insulin resistance. RESULTS: Insulin sensitivity was not different between REL and CON. Fasting glucose, insulin, triglycerides and PYY were also not different between groups. However, the postprandial incremental area under curve (AUC) of PYY was significantly lower in REL after the high carbohydrate (HCHO) meal (+27.3 vs +60.6% increase from baseline, P=0.038). The AUC of insulin during HCHO meal correlated negatively with both AUC and fasting level of PYY (r=-0.58 and -0.60, respectively, P<0.05). CONCLUSIONS: A blunted postprandial PYY secretion is observed in a very early stage in the development of T2D in genetically susceptible individuals. This defect precedes the presence of insulin resistance and adiposity, and could therefore predispose to the development of T2D.

Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes.

OBJECTIVE: To investigate levels of components of the alternative pathway of complement, and of two activation products, ASP and Bb, in persons ranging in insulin resistance both fasting and following the consumption of a high-fat, low-carbohydrate meal. SUBJECTS: Healthy controls (n = 17) and normoglycaemic first-degree relatives of patients with type II diabetes (n = 15). MEASUREMENTS: All subjects had normal glucose tolerance. Blood was collected for the measurement of plasma glucose, insulin, triglycerides and free fatty acids. Body composition was assessed with dual energy X-ray absorptiometry (DEXA) and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Basal and postprandial values over 6 h were determined for plasma C3, B, D, Bb and ASP. Basal levels of C1q, C4 and CRP were also determined. RESULTS: Controls did not differ significantly from the relatives of patients with type II diabetes for any metabolic parameter except in their degree of insulin resistance and central fat (kg). Across all subjects, basal levels of C3, but no other complement protein, were correlated with insulin resistance. Native complement proteins, but not ASP or Bb, were correlated with body mass index and the amount (kg) of central fat. Basal levels of C3 and factor B were significantly higher in the relatives group, whereas factor D and the classical pathway proteins C1q and C4 did not differ between the two groups. Postprandially, levels of factor D were significantly reduced in both groups. ASP levels also fell postprandially, the decline achieving significance in the relatives group. CONCLUSIONS: Elevated levels of C3 and factor B in the diabetic relatives group may have resulted from increased synthesis by adipose tissue. There was no evidence of alternative pathway activation in response to a fat meal in terms of ASP or Bb production, or significant consumption of C3 and factor B. These data do not support an essential requirement of the hypothesis that ASP is produced in response to the intake of fat.

Circulating fatty acids, non-high density lipoprotein cholesterol, and insulin-infused fat oxidation acutely influence whole body insulin sensitivity in nondiabetic men.

Circulating lipids and tissue lipid depots predict insulin sensitivity. Associations between fat oxidation and insulin sensitivity are variable. We examined whether circulating lipids and fat oxidation independently influence insulin sensitivity. We also examined interrelationships among circulating lipids, fat oxidation, and tissue lipid depots. Fifty-nine nondiabetic males (age, 45.4 +/- 2 yr; body mass index, 29.1 +/- 0.5 kg/m(2)) had fasting circulating nonesterified fatty acids (NEFAs) and lipids measured, euglycemic-hyperinsulinemic clamp for whole body insulin sensitivity [glucose infusion rate (GIR)], substrate oxidation, body composition (determined by dual energy x-ray absorptiometry), and skeletal muscle triglyceride (SMT) measurements. GIR inversely correlated with fasting NEFAs (r = -0.47; P = 0.0002), insulin-infused NEFAs (n = 38; r = -0.62; P < 0.0001), low-density lipoprotein cholesterol (r = -0.50; P < 0.0001), non-high-density lipoprotein cholesterol (r = -0.52; P < 0.0001), basal fat oxidation (r = -0.32; P = 0.03), insulin-infused fat oxidation (r = -0.40; P = 0.02), SMT (r = -0.28; P < 0.05), and central fat (percentage; r = -0.59; P < 0.0001). NEFA levels correlated with central fat, but not with total body fat or SMT. Multiple regression analysis showed non-high-density lipoprotein cholesterol, fasting NEFAs, insulin-infused fat oxidation, and central fat to independently predict GIR, accounting for approximately 60% of the variance. Circulating fatty acids, although closely correlated with central fat, independently predict insulin sensitivity. Insulin-infused fat oxidation independently predicts insulin sensitivity across a wide range of adiposity. Therefore, lipolytic regulation as well as amount of central fat are important in modulating insulin sensitivity.

Do gene-environment interactions influence fasting plasma lipids? A study of twins.

BACKGROUND: The aims of this study were to determine the influence of smoking, alcohol consumption, physical activity and hormone replacement therapy (HRT) on lipids, independently of genetic factors, and to detect whether gene-environment interactions influence these associations. MATERIALS AND METHODS: Fasting plasma total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins AI and B and lipoprotein(a) were measured in 685 female twins (96 monozygotic, 230 dizygotic pairs and 33 singletons). RESULTS: Smokers had higher triglyceride and lower HDL cholesterol levels than never-smokers (P < 0.001). After controlling for genetic influences, smoking accounted for 0.35 mmol L(-1) and 0.22 mmol L(-1) differences in triglyceride and HDL cholesterol levels, respectively (P < 0.005), remaining significant after excluding alcohol-discordant twin pairs. In a gene-environment interaction analysis, the association between smoking and triglycerides was exaggerated in subjects at high genetic risk of hypertriglyceridaemia (interaction P=0.04). All levels of alcohol consumption were associated with higher HDL cholesterol levels than abstinence, but only moderate alcohol consumers had lower LDL cholesterol and triglyceride levels. In monozygotic twins concordant for smoking, an alcohol intake > 10 units week(-1) accounted for a 0.32 mmol L(-1) difference in LDL cholesterol, independently of genetic effects (P=0.04). In postmenopausal women, those using HRT had 0.54 mmol L(-1) lower LDL cholesterol and 0.21 micromol L(-1) lower lipoprotein(a) levels than nonusers (P < 0.001 and P=0.04, respectively); these differences were attenuated after accounting for genetic effects in monozygotic twins. Although physically active subjects had higher levels of HDL cholesterol than nonactive subjects, this was nonsignificant after adjusting for genetic factors. CONCLUSIONS: Smoking-induced aberrations in HDL cholesterol and triglycerides and alcohol-related differences in LDL cholesterol were independent of genetic influences. The association between smoking and hypertriglyceridaemia was accentuated in high genetic risk individuals.