Regulators of glucose and lipid metabolism in skeletal muscle and serum : implications for obesity and type 2 diabetes

Type 2 diabetes mellitus (T2DM) has become a growing worldwide problem of public health importance. Insulin resistance is commonly associated with obesity and a key factor mediating the progression to T2DM. The failure of insulin-sensitive peripheral tissues to respond to insulin results in an increase in serum glucose levels that leads to an impaired homeostatic state. Skeletal muscle plays a crucial role in maintaining glucose metabolism. Impairments in both glucose and lipid metabolism arising from a dysregulation of hormones, free fatty acids, or other factors contribute significantly to the pathogenesis of T2DM. The roles of several circulating metabolites in the development of insulin resistance have been described. However the molecular mechanisms involved in skeletal muscle insulin resistance remain poorly defined. Furthermore, the biological interactions between skeletal muscle, novel circulating factors, and lifestyle factors such as exercise in the regulation of glucose and lipid metabolism need to be investigated. This thesis aims at examining the role of novel regulators of glucose and lipid metabolism, uncovering the molecular targets involved in the development of skeletal muscle insulin resistance, and describing their clinical implications in obesity and T2DM. Physical exercise has beneficial effects on glucose and lipid metabolism and hence improves cardiovascular risk factors. In Study I, we report differential effects of Nordic walking (low-moderate intensity exercise) on cardiovascular risk factors in normal and impaired glucose tolerant individuals. We provide evidence to support the recommendation of a more intense and supervised exercise modality for significant improvements in cardiovascular risk factors. Fibroblast growth factor (FGF)-21 is a member of the FGF family that plays a role in a variety of endocrine functions, including the regulation of glucose and lipid metabolism. Observations from animal models have suggested a potential therapeutic role of this growth factor in T2DM. In Study II, we provide evidence for direct effects of FGF-21 in skeletal muscle glucose uptake. Using cell-surface photolabeling of human myotubes, we report enhanced glucose transporter-1 abundance at the cell membrane, coincident with increased basal and insulin-stimulated glucose uptake. We further confirm a paradoxical increase in serum FGF-21 in T2DM in humans, and identify BMI as the strongest independent predictor of FGF-21 serum levels. The mechanisms controlling the metabolic actions of FGF-21 are currently being resolved. Signal transducer and activator of transcription factor 3 (STAT3) is involved in cytokine- and nutrient-induced insulin resistance. The role of STA T3 in the development of skeletal muscle insulin resistance and T2DM pathogenesis is incompletely defined. In Study III, we report an increased STAT3 phosphorylation in T2DM. Using palmitate and STAT3 specific siRNA treatment of myotubes in vitro, we provide evidence for the role of STAT3 in the development of lipid-induced skeletal muscle insulin resistance. Collectively, the work presented in this thesis contributes to the understanding of various regulators of glucose and lipid metabolism from the whole body physiology context to molecular mechanisms in skeletal muscle. Metabolic alterations result from the interplay between biological processes within the cells, tissues and organs. These alterations may translate into ill health such as T2DM. Information from Translational studies like the ones presented in this thesis will help to identify molecules with both clinical significance and therapeutic potential

Is the FINDRISC Tool Useful in Screening Type 2 Diabetes and Metabolic Syndrome in an African Setting? Experience among Young Adults in Urban Tanzania

Background: Simple and less costly screening tools are needed to combat the rising non-communicable diseases epidemic. This study aimed to evaluate the utility of The Finnish Diabetes Risk Score (FINDRISC) as a screening tool for prediabetes, T2D, and metabolic syndrome (MetS) in a population of young adults in urban Mwanza, Tanzania. Methods: A cross-sectional community-based study was conducted among participants aged 18–35 years. The FINDRISC questionnaire was used to collect data and compute the FINDRISC scores for each participant. Socio-demographic, anthropometric, blood glucose, and lipid profiles data were collected accordingly. Results: A total of 259 participants were recruited into the study. The median age was 21 years (IQR 19–27), and more than half 60.2% (156) were females. In total, 32.8% (85) of the participants had at least a slightly elevated risk of developing T2D in 10 years’ time. Compared to the Oral Glucose Tolerance Test (OGTT), FINDRISC had a sensitivity and specificity of 39.1% and 69.2%, respectively (aROC = 0.5). The FINDRISC score significantly correlated with MetS (p = 0.001). Conclusion: In this study, FINDRISC has shown low sensitivity and specificity in the screening of pre-diabetes/T2D. However, it has potential utility in the screening of MetS in a young-adult population

A stakeholder analysis of the road transport system in Tanzania using a STAMP control structure

The way the road transport system is developed in a country affects safety. This study aims to identify the roles and relationships of road transport stakeholders and to explore the understanding of control and feedback mechanisms and associated gaps influencing road safety. A System-Theoretic Accident Model and Processes (STAMP) model was applied to document and interview data (n = 30). Participants emphasised the hindrance of overlapping mandates among stakeholders on the road transport system’s operations and underlined the roles of coalitions for road safety as system enablers. Further, the withdrawal of some controls by international agencies can increase system vulnerability. Most importantly, critical control and feedback gaps were shown to increase risks for safety within the road transport system. The findings underscore the complexity of the road transport system and add to the discussion on a system’s approach to road safety. Practitioner summary: Using a STAMP methodology, we extensively studied the road transport system in Tanzania. Road transport stakeholders were identified through the review of documents, interviews were conducted, and the main findings were discussed. Control and feedback mechanisms and associated gaps were critically presented, recommendations were proposed, and policy implications were suggested.</p

Adiposity Is a Key Correlate of Circulating Fibroblast Growth Factor-21 Levels in African Males with or without Type 2 Diabetes Mellitus

Background. Fibroblast growth factor-21 is an endocrine regulator with therapeutic and diagnostic potential. The levels and pattern of circulating FGF-21 have been described mainly in European and Asian populations. Given its strong association with adiposity, and the reported ethnic variabilities in body composition, examining FGF-21 in an African population is crucial. Methods. We measured levels of circulating FGF-21 in 207 overweight and obese Tanzanian males with or without type 2 diabetes mellitus (T2DM), and using statistical approaches, we explored their relationship with anthropometric and biochemical parameters. Results. Consistent with previous reports from European and Asian populations, we found higher levels of FGF-21 in people with T2DM compared to those without the disease. Based on statistical models, measures of adiposity explained up to 59% of the variability in FGF-21 levels in the circulation. Conclusion. Levels of circulating FGF-21 in overweight and obese African males are higher in T2DM and strongly correlate with measures of adiposity

Association of HIV and ART with cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis.

BACKGROUND: Sub-Saharan Africa (SSA) has the highest burden of HIV in the world and a rising prevalence of cardiometabolic disease; however, the interrelationship between HIV, antiretroviral therapy (ART) and cardiometabolic traits is not well described in SSA populations. METHODS: We conducted a systematic review and meta-analysis through MEDLINE and EMBASE (up to January 2012), as well as direct author contact. Eligible studies provided summary or individual-level data on one or more of the following traits in HIV+ and HIV-, or ART+ and ART- subgroups in SSA: body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGs) and fasting blood glucose (FBG) or glycated hemoglobin (HbA1c). Information was synthesized under a random-effects model and the primary outcomes were the standardized mean differences (SMD) of the specified traits between subgroups of participants. RESULTS: Data were obtained from 49 published and 3 unpublished studies which reported on 29 755 individuals. HIV infection was associated with higher TGs [SMD, 0.26; 95% confidence interval (CI), 0.08 to 0.44] and lower HDL (SMD, -0.59; 95% CI, -0.86 to -0.31), BMI (SMD, -0.32; 95% CI, -0.45 to -0.18), SBP (SMD, -0.40; 95% CI, -0.55 to -0.25) and DBP (SMD, -0.34; 95% CI, -0.51 to -0.17). Among HIV+ individuals, ART use was associated with higher LDL (SMD, 0.43; 95% CI, 0.14 to 0.72) and HDL (SMD, 0.39; 95% CI, 0.11 to 0.66), and lower HbA1c (SMD, -0.34; 95% CI, -0.62 to -0.06). Fully adjusted estimates from analyses of individual participant data were consistent with meta-analysis of summary estimates for most traits. CONCLUSIONS: Broadly consistent with results from populations of European descent, these results suggest differences in cardiometabolic traits between HIV-infected and uninfected individuals in SSA, which might be modified by ART use. In a region with the highest burden of HIV, it will be important to clarify these findings to reliably assess the need for monitoring and managing cardiometabolic risk in HIV-infected populations in SSA

HIV treatment is associated with a two-fold higher probability of raised triglycerides: Pooled Analyses in 21 023 individuals in sub-Saharan Africa.

Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TG) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations. Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (&gt;2.3 mmol/L) was analysed using regression models. Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51-2.77, I2=45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies. Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SSA