Male reproductive success in many mammals depends on their ability to allocate sufficient energetic resources to mating competition. Such costs are particularly pronounced in species with high levels of sexual body dimorphism, intense polygyny and distinct breeding seasons. I tested the hypothesis that male reproductive effort incurs significant energetic costs in wild chimpanzees (Pan troglodytes), a species with moderate sexual dimorphism, promiscuous mating and lack of breeding seasonality. My field studies combined behavioral observations on male chimpanzee behavior with non-invasive sampling of urinary C-peptide (UCP). UCP is a biomarker of insulin production that indexes individual energy balance. This dissertation contributes to the understanding of UCP as an energy assay by (1) validating the application of UCP for assessing dietary quality in bonobos (Pan paniscus) at Kokolopori, DRC and (2) providing a detailed assessment of diurnal variation in UCP levels in relation to short-term changes in food intake in chimpanzees at Kanyawara, Kibale NP, Uganda. I used UCP measurements in conjunction with full-day focal observations of male chimpanzees to assess the energetic costs of male-male competition for status and mating opportunities. Data on feeding time and rates of aggression suggested that males experience a reduction in energy intake and an increase in energy expenditure when highly attractive parous females were in estrus. UCP data supported these conclusions because males had lower UCP levels on mating days, and rates of aggression were negatively associated with UCP levels. Mean daily party size was also associated with low UCP levels, controlling for the presence of estrous females. Habitat-wide availability of preferred fruits was positively associated with male rates of aggression suggesting that energy availability mediates male investment towards energetically costly competitive behaviors. Contrary to expectations males who were most successful in obtaining copulations (high-ranking males) did not suffer higher energetic costs than lower-ranking males during periods of mating competition. Costs or reproductive effort include both direct competition for matings and long-term competition over social status. Maintenance of social rank over long periods appears to be particularly important in this slow-reproducing, long-lived and nonseasonally breeding primate. / Human Evolutionary Biology

Several studies have reported beneficial effects of C-peptide supplementation in diabetic patients and animal models of insulinopenic diabetes. However, it is also established that good glycemic control is essential to minimize the risk of diabetes-induced complications. This thesis investigates potential mechanisms for the beneficial effect of C-peptide on glomerular hyperfiltration, and a novel, painless route of insulin administration. The results demonstrate that both C-peptide and its C-terminal penta-peptide sequence reduce the diabetes-induced glomerular hyperfiltration within an hour. The results also indicate that C-peptide possibly reduces diabetes-induced hyperfiltration via three different mechanisms: 1. Constriction of the afferent arteriole was demonstrated on isolated vessels from diabetic mice. 2. A net dilation of the efferent arteriole was evident in vivo. 3. Inhibition of the Na+/K+-ATPase was demonstrated in vivo in diabetic rats as well as in vitro on isolated proximal tubular cells from diabetic rats. All these mechanisms are known regulators of the net glomerular filtration pressure. The last part of this thesis demonstrates that intradermal administration with a newly developed patch-like microneedle device results in similar insulin concentration compared to standard subcutaneous delivery. These findings provide an insight for the beneficial effects of C-peptide on diabetic kidney function, and shows that this effect can be achieved by infusion of the C-terminal penta-peptide sequence alone. This thesis also presents a novel, painless alternative to insulin injections that is controllable, requires minimal training, and therefore presents several advantages compared to current standard therapy.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2006. / Härtill 4 uppsatser.

Diabetes prevalence is increasing in our ageing and increasingly obese society. Diabetes is a heterogeneous condition, and challenges remain in all aspects of its management - from diagnosis through to optimising treatment, to managing complications. Increasing age brings altered physiological responses to disease, treatments and complications - and there may be more wide-ranging considerations such as dietary, mobility, dependency or cognition, to name just a few. Hypoglycaemia is one of the most important potential side-effects of insulin-therapy, and elderly adults are at particular risk from its consequences. Insulin-treated patients may have long-standing Type 1 diabetes, or have Type 2 diabetes which has progressed to requiring insulin treatment, due to progressive beta cell deficiency. Even within this group of patients, there is heterogeneity, and assessment of risks can be challenging. Endogenous insulin levels can be assessed by measuring C-peptide. Recent advances in this has meant this is much more practical, enabling assessment of endogenous levels in large numbers of patients more feasible, and hence allowing important questions to be addressed. In the context of older patients, particularly interesting questions are whether patients with long-standing Type 2 diabetes can develop severe insulin deficiency, and whether absolute/severe endogenous insulin levels have an impact on treatment or complications of diabetes within insulin-treated cohorts – such as hypoglycaemia. This may thence raise the question of whether C-peptide measurement could potentially be used as an extra clinical tool for risk assessment in a patient population which can be tricky to manage at times. The aim of this thesis is thus to explore some of the issues around management of diabetes in the elderly: in particular hypoglycaemia, and use of C-peptide to more fully assess patients and consider a possible role for it in routine clinical care of some patients. Chapter 1 puts the thesis in context, firstly reviewing hypoglycaemia in the elderly in general, and then considering aspects of endogenous insulin levels and C-peptide measurement. Chapter 2 addresses the problem of recognition of hypoglycaemia in an elderly population, using primary care records and documented symptoms at consultations. Are we missing hypoglycaemia in this population? Accurate diagnosis of diabetes is crucial for getting people on the right treatment guidelines, and can be challenging. Chapter 3 uses a spot urine measure of C-peptide to test for the first time the accuracy of the UK Practical Classification Guidelines (published by the Royal College of General Practitioners and NHS Diabetes). Progressive insulin deficiency in Type 2 diabetes is the main reason people with long-standing Type 2 diabetes may eventually require insulin treatment. Chapter 4 uses the spot urine measure of C-peptide as a screening tool to assess if insulin-treated people with a clinical diagnosis of Type 2 diabetes may develop absolute insulin deficiency. Even more practical than a spot urine test to measure C-peptide, could be a random non-fasting blood measure of C-peptide, which could thus be measured when patients have their routine blood tests done in the community or outpatient appointments. Chapter 5 looks at how such a measure correlates with the gold-standard mixed meal tolerance test C-peptide measure. Severe insulin deficiency in Type 1 diabetes has been correlated with increased complications including hypoglycaemia, but the impact of endogenous insulin levels has not been assessed greatly in Type 2 diabetes. Chapter 6 reports a study looking into this possible relationship, using hypoglycaemia questionnaire responses from a large number of community-dwelling insulin-treated adults (of both diagnoses), in the context of their clinical diabetes diagnosis and their random non-fasted blood C-peptide levels. Chapter 7 assesses in more detail the rates of hypoglycaemia in a small group of insulin-treated patients with a clinical diagnosis of Type 2 diabetes, selected on the basis of their endogenous C-peptide levels. As well as subjective assessment of their hypoglycaemia experience using questionnaires, continuous glucose monitoring was used to objectively assess their rates of hypoglycaemia and glucose variability. Chapter 8 pulls all the above chapters together, summarising them in the context of other research, discussing their limitations and possible areas for future research, and their implications for now for clinical practice.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Insulin resistance is common among obese adolescents; however, the extent of this problem is not clear. We conducted a systematic review of PubMed-Medline, CINAHL, The Web of Science, EMBASE and Scopus for observational studies evaluating components defining insulin resistance (insulin, C-peptide and homeostatic model assessment-insulin resistance [HOMA-IR]) in obese adolescents (12–18 years) versus non-obese adolescents. Our systematic review and meta-analysis followed the PRISMA guidelines. Data were combined using a random-effects model and summary statistics were calculated using the mean differences (MDs). 31 studies were included (n = 8655). In 26 studies, fasting insulin levels were higher in obese adolescents when compared to non-obese adolescents (MD = 64.11 pmol/L, 95%CI 49.48–78.75, p < 0.00001). In three studies, fasting C-peptide levels were higher in obese adolescents when compared to non-obese adolescents (MD = 0.29 nmol/L, 95%CI 0.22–0.36, p < 0.00001). In 24 studies, HOMA-IR values were higher in obese adolescents when compared to non-obese adolescents (MD = 2.22, 95%CI 1.78–2.67, p < 0.00001). Heterogeneity of effects among studies was moderate to high. Subgroup analyses showed similar results to the main analyses. Circulating insulin and C-peptide levels and HOMA-IR values were significantly higher in obese adolescents compared to those non-obese. / Revisión por pares

The purpose of this report is to compare seven different methods for biomarker detection and quantification based on previously published papers. The methods investigated are ELISA, LC-MS/MS, UPLC-MS/MS, LC-IM/MS, IA-LC-MS/MS, MSIA-HR/AM, HTRF and AlphaLISA ® . The focus lies on biomarkers relevant for diabetes, obesity and cardiovascular diseases.Namely insulin, proinsulin, glucagon and C-peptide. Particular significance is assigned to the comparison of the currently widest used method, ELISA, with various types of LC-MS/MS. The report concludes ELISA being superior to LC-MS/MS methods in terms of recovery and precision, while LC-MS/MS is superior in accuracy, multiplexing, specificity, throughput and sample cost. This suggests that different types of LC-MS/MS has the potential to gain momentum in the field of biomarker quantification if they become more available.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Diabetes mellitus is presently recognized as the sixth leading cause of death in the United States, affecting over 20 million people. Diabetes is a condition characterized by high blood glucose due to an insulin deficiency or resistance. Type I, which comprises 5-10% of all cases, results from the destruction of pancreatic beta cells in the islets of Langerhans. The current treatment for type I diabetes is insulin administration through injection or pump. Purification, production, and storage of this insulin proves to be quite costly. By producing biologically functional insulin with oral delivery capabilities through chloroplast genetic engineering, many of these costs could be cut back. In addition, the possibility of providing the C-peptide currently lacking in commercially available insulin becomes available. The Daniell lab inserted cholera toxin B-subunit (CTB) fused proinsulin, containing three furin cleavage sites, (CTB-pins Fx3) into the tobacco chloroplasts of Petit Havana via particle gun bombardment. The insertion of three furin cleavage sites along with fusion to CTB will enable the insulin to sustain function when orally administered. Transgenic plants from the second generation were then analyzed and tested for quantification of the CTB-pins Fx3 gene. Tobacco leaves of varying ages were compared to determine expression levels. The resulting data is pertinent for future production of both orally deliverable insulin and more cost effective injectable insulin.