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Att leva med diabetes typ-1 innebär att sprutstick och kanyler blir en del av vardagen som idagsläget inte kan väljas bort. Insulintekniken är inte anpassad efter en varierad livsstil ochdärför kan få många drabbade att känna sig begränsad i sin vardag.I mitt examensprojekt har jag försökt skapa en designlösning som kan ge diabetiker en friareanvändning av diabetesteknik, utan att hindras av receptutskrivningar och läkarbesök.Duo skapar en modern mer hållbar lösning för diabetestekniken, både ur en hälso- ochmiljösynpunkt. Projektet har gjorts i samarbete med Medtronic samt Ung Diabetes i Umeå. / Living with diabetes type-1 means that needles and cannulas become a part of the daily life,that today cannot be excluded. The insulin technology is not fitted for a versatile lifestyle andcan therefore make the person living with the disease feel limited in their daily life.In my degree project I have aimed to create a design solution that can give people living withdiabetes a more free use of diabetes equipment, without being kept back by prescriptionsand doctor appointments. Duo creates a modern, more sustainable solution for diabetesequipment, both from a health and environmental point of view. The project was made incollaboration with Medtronic and Ung Diabetes (Young Diabetes) in Umeå.

Call number: LD2668 .T4 1966 F854 / Master of Science

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Diabetes Mellitus is characterized by high blood sugar and is caused by resistance to (type 2) or insufficiency of (type 1) the pancreatic β-cell hormone insulin. Most commonly, type 2 diabetes is associated with obesity whereas type 1 diabetes is largely a result of immune-mediated destruction of the β-cell. One rare but significant cause of type 2 diabetes is excess blood glucocorticoid levels (Cushing’s syndrome). High circulating glucocorticoids potently induce metabolic disorders including peripheral insulin resistance in key metabolic tissues (muscle, liver and fat) as well as directly suppressing β-cell function and can precipitate type 2 diabetes. However, in common forms of metabolic syndrome (visceral obesity, type 2 diabetes, increased cardiovascular disease risk) it appears that amplification of local tissue glucocorticoid action by increased levels of the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), particularly in adipose tissue, is a key driver of the adverse metabolic phenotype rather than altered circulating glucocorticoid levels. 11β-HSD1 is also elevated in pancreatic islets from obese rodents. This thesis aimed to determine the role of 11β-HSD1 in pancreatic islets (β-cells) under normal conditions and its potential pathogenic role in the development of diabetes. We first determined that 11β-HSD1 acted primarily as a reductase (amplifying glucocorticoid action) in pancreatic islets. We then determined that islet 11β-HSD1 transcription is under the control of the promoters that express in other tissues like liver. Islet 11β-HSD1 is significantly regulated by factors relevant to the diabetic state; high glucose and insulin suppressed whereas fatty acids and TNFα increased 11β-HSD1 activity. To test whether the high islet 11β-HSD1 found in obese rodents was directly diabetogenic, we generated transgenic mice specifically overexpressing β-cell 11β-HSD1 under the mouse insulin promoter (MIP-HSD1 mice) in a mouse strain prone to develop β-cell failure when subjected to diabetic challenge (eg. chronic high fat feeding). Unexpectedly, MIP-HSD1tg/+ mice (expressing ~2 fold elevated 11β-HSD1 activity) exhibited markedly improved β-cell insulin secretory responses, whereas MIP-HSD1tg/tg mice had partially impaired β-cell insulin secretory function in vivo and in vitro. Moreover, MIP-HSD1tg/+ mice completely resisted the mild hyperglycaemia induced by multiple-low doses of the β-cell toxin streptozotocin (40mg/kg i.p. for 5 days) and partially resisted the profound hyperglycaemia induced by a single high dose of streptozotocin (180mg/kg). Notably, MIP-HSD1tg/+ mice exhibited lower macrophage infiltration (MAC-2) and higher T-regulatory cell (Foxp3) infiltration after these challenges with evidence of increased insulin-positive cells and maintenance of normal levels of proliferation-competent β-cells. Overall, MIP-HSD1tg/tg exhibited a partial protection from the streptozotocin challenge. Modestly increased 11β-HSD1 expression in β-cells unexpectedly supports compensatory insulin hypersecretion preventing type 2 diabetes and protects β-cells from inflammatory mediated damage in the setting of type 1 diabetes. Above a protective threshold, elevated β-cell 11β-HSD1 may result in β-cell dysfunction and diabetes. These findings have important implications for the currently advocated therapeutic strategies to inhibit 11β-HSD1 in the context of obesity and diabetes.

These studies investigated 1) mechanisms underlying the well-established reduction in orthostatic tolerance (OT) that occurs in humans during heat stress (HS) relative to normothermia (NT) with particular focus on determining factors contributing to the high degree of inter-individual variability in this phenomenon; and 2) influence of obesity on OT, and mechanisms underlying reduced OT, should it exist. In Study #1, OT was assessed during lower body negative pressure (LBNP), and quantified with a cumulative stress index (CSI). Differences in CSI (CSIdiff) between thermal conditions were used to categorize individuals most (LargeDiff) and least (SmallDiff) affected by HS (P<0.001). Cerebral perfusion [indexed as middle cerebral artery blood velocity (MCA Vm̳̳e̳a̳n̳)] was reduced during HS compared to NT (P<0.001); however, the magnitude of reduction did not differ between groups (P=0.51). In the initial stage of LBNP during HS (LBNP20), MCA Vm̳̳e̳a̳n̳ and end-tidal CO₂ (PETC̳O̳₂) were reduced, and heart rate (HR) was higher in the LargeDiff group compared to SmallDiff group (all P<0.05); yet, mean arterial pressure was similar (P=0.23) suggesting impaired mechanisms regulating MCA Vm̳̳e̳a̳n̳ may affect OT. In Study #2, mechanisms of cerebrovascular control were compared in LargeDiff and SmallDiff individuals. Although estimates of cerebral autoregulation (CA) and cerebrovascular reactivity to CO₂ were improved and reduced respectively, during HS compared to NT (all P<0.05), no relationship existed between CA or cerebral reactivity to hypocapnia and CSIdiff (all P>0.05). In Study #3, OT was lower in obese compared to non-obese individuals (P<0.01), and BMI was negatively correlated with CSI (R = -0.47; P < 0.01). HR was elevated at rest and in every level of LBNP (all P<0.05) in obese; yet, peak HR during LBNP was similar between groups (P=0.90). MCA Vm̳̳e̳a̳n̳ and cerebral vascular conductance were similar at rest and during LBNP (both P>0.05), and CA was similar between groups (P>0.05). In summary, a high HR prior to-, and a high HR and reduced MCA Vm̳̳e̳a̳n̳ at the onset of an orthostatic challenge result in reduced OT during HS in healthy individuals; however, reduced OT in obese is related to a higher %peak HR at rest. / text

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