Chronic kidney disease is defined as the appearance of kidney functional or structural injury. Cyclooxygenase and prostaglandin E2 have been implicated in the pathogenesis of diabetic nephropathy, the leading cause of chronic kidney disease. Beneficial in certain settings, inhibition of the cyclooxygenase pathway can however be detrimental in patients with compromised cardiac or renal function. Moreover, the quest for new therapies to treat diabetic nephropathy is hampered by the lack of appropriate rodent models. This doctoral thesis is a culmination of three studies, the first to determine the role of the prostaglandin E2 EP1 receptor in diabetic nephropathy, the second to elucidate the vascular prostaglandin E2 EP4 receptor’s role in hypertension and lastly to establish and characterise a novel mouse model of diabetic nephropathy. The goal being to uncover new therapeutic avenues for the treatment of CKD, its causes and/or complications.

Neuropathy is one of the main long term complications of diabetes affecting 30-50% of patients. It is the major contributing factor for foot ulceration with a life time risk which may be as high as 25%. Hence neuropathy leads to reduced pain and pressure perception, anatomic deformities and an impaired microcirculation. More specifically, unperceived minor trauma results in cutaneous injury which when combined with an inadequate pressure induced vasodilator response leads to tissue breakdown and ulceration. Once ulcers form, healing may be delayed or difficult to achieve, particularly if infection occurs in the deeper tissues and bone which can then lead to amputation. In the UK, South Asians (people originating from India, Pakistan and Bangladesh) have an excess mortality for coronary artery disease (CAD), stroke and end-stage renal disease when compared to white Europeans. However, it has been shown that South Asian people with type 2 diabetes in the UK are only one third as likely to have a foot ulcer compared with White European diabetic patients. This has been attributed to lower levels of peripheral neuropathy in Asians, but has not been systematically explored in detail. In the present study, both neurological and vascular deficits in a group of South Asian and European patients with type II diabetes have been assessed. The results demonstrate that: • South Asian diabetic patients have poorer glycaemic control, but paradoxically lower triglycerides. This finding may be relevant to the finding that they have a lower incidence of neuropathy, as triglycerides have been related to neuropathy and foot ulceration. • South Asians compared to Europeans have better small fibre function and a trend for better structure (Intra epidermal nerve fibre density and corneal nerve morphology) and large fibre function assessed with nerve conduction studies. • South Asians have higher foot skin oxygenation and hyperaemic blood flow response to heating. • South Asians have a thicker epidermis and a trend for a better capillary density. Therefore these alterations may protect South Asians from the development of foot ulceration.

Indiana University-Purdue University Indianapolis (IUPUI) / Transforming growth factor β-activated kinase 1 (TAK1), a hub kinase at the convergence of multiple signaling pathways, is critical to the development of the central nervous system and has been found to play a role in cell death and apoptosis. TAK1 may have the potential to elucidate mechanisms of cell cycle and neurodegeneration. The Belecky-Adams laboratory has aimed to study TAK1 and its potential roles in cell cycle by studying its role in chick retinal development as well as its possible implication in the progression of diabetic retinopathy (DR). Chapter 3 includes studies that explore TAK1 in a study in chick retinal development and TAK1 in in vitro studies in retinal microglia. Using the embryonic chick, immunohistochemistry for the activated form of TAK1 (pTAK1) showed localization of pTAK1 in differentiated and progenitor cells of the retina. Using an inhibitor or TAK1 activite, (5Z)-7-Oxozeaenol, in chick eye development showed an increase in progenitor cells and a decrease in differentiated cells. This study in chick suggests TAK1 may be a critical player in the regulation of the cell cycle during retinal development. Results from experimentation in chick led to studying the potential role of TAK1 in inflammation and neurodegeneration. TAK1 has previously been implicated in cell death and apoptosis suggesting that TAK1 may be a critical player in inflammatory pathways. TAK1 has been implicated in the regulation of inflammatory factors in different parts of the CNS but has not yet been studied specifically in retina or in specific retinal cells. Chapter 2 includes studies from the Belecky-Adams laboratory of in vitro work with retinal microglia. Retinal microglia were treated with activators and the translocation to the nucleus of a downstream factor of TAK1 was determined: NF-kB. Treatment of retinal microglia in the presence of activators with TAKinib, an inhibitor of TAK1 activation, revealed that TAK1 inhibition reduces the activation of downstream NF-kB. Together this data suggests that TAK1 may be implicated in various systems of the body and further studies on its mechanisms may help elucidate potential therapeutic roles of the kinase.

Background: Hypoglycemia is a commonly encountered metabolic state in the patient population. It can be medically defined as a blood sugar <70mg/dL in a diabetic patient or <50mg/dL in a non-diabetic patient. It is less frequently seen in non-diabetics due to the body’s ability to autoregulate insulin administration. Common symptoms are sweating, tremors, palpitations, dizziness, drowsiness, and confusion. If left untreated, these symptoms can progress to seizures, arrythmias, or other complications that ultimately lead to death. Objective: To highlight the possible causes of hypoglycemia and the appropriate work-up for normally euglycemic patients. Case Description: We herein report a case of hypoglycemia in a 36-year-old female with Lupus related end-stage renal disease on hemodialysis via Ash-catheter who presented with peritonitis due to a defunct peritoneal dialysis catheter. The patient was found to be bacteremic; therefore both catheters were removed and antibiotics were started. Repeat blood cultures showed no growth for 48 hours, so the patient was held fasting at midnight for placement of a new catheter. On the day of surgery, she registered multiple blood sugar readings as low as 15mg/dL. Her symptoms were limited to drowsiness and shortness of breath. She was given four D50 boluses, glucagon IV, and a D5 drip that was adjusted to a D15 drip to stabilize her blood sugar. It was discovered that at an admission two months ago, the patient had a few readings in the 30s. She denied any recollection of this and claimed to have been asymptomatic. She also denied a history of low blood sugars and a diagnosis of diabetes. In surgery that day, the patient went into cardiac arrest on the operating table after being sedated. She was resuscitated after one round of chest compressions, and her catheter was placed. During the episodes of low blood sugar, specific labs were drawn for the work-up of hypoglycemia (glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, insulin antibodies, and sulfonylurea/meglitinide screen), but results yielded inconclusive values that prevented a diagnosis. The patient’s blood sugars became steady once her diet was restarted, and she was discharged in stable condition to a rehab facility after cautionary counseling was given. Discussion: This case highlights an optimal way to work-up a patient with new onset hypoglycemia, focusing on patient history and drawing the appropriate labs during hypoglycemic episodes. The specific labs listed above can be used to differentiate between various causes of hypoglycemia (exogenous insulin administration, an insulin secreting tumor [insulinoma], insulin antibodies, insufficient cortisol or glucagon levels, or improper sulfonylurea/meglitinide use) by comparing them to standards. If labs are unable to be obtained, a 72-Hour Fast can be conducted to create a controlled environment, and a Glucagon Tolerance Test can further explore if the cause of hypoglycemia is insulin related. The goal of all of this testing is to be able to identify and treat the underlying cause of the hypoglycemia and prevent future episodes and the complications that accompany it.

Baroreflex control of heart rate (HR) is impaired in diabetes mellitus. We hypothesized that diabetes mellitus induced functional changes of neural components at multiple sites within the baroreflex arc. Type 1 diabetic mice (OVE26) and FVB control mice were anesthetized. Baroreflex-mediated HR responses to sodium nitroprusside- (SNP) and phenylephrine- (PE) induced mean arterial blood pressure (MAP) changes were measured. Baroreceptor function was characterized by measuring the percent (%) change of baseline integrated aortic depressor nerve activity (Int ADNA) in response to SNP- and PE-induced MAP changes. The HR responses to electrical stimulation of the left aortic depressor nerve (ADN) and the right vagus nerve were assessed. Compared with FVB control mice, we found in OVE26 mice that (1) baroreflex-mediated bradycardia and tachycardia were significantly reduced. (2) The baroreceptor afferent function in response to MAP increase did not differ, as assessed by the parameters of the logistic function curve. But, the inhibition of Int ADNA in response to MAP decrease was significantly attenuated. (3) The maximum amplitude of bradycardic responses to right vagal efferent stimulation was augmented. (4) In contrast, the maximum amplitude of bradycardic responses to left ADN stimulation was decreased. Since Int ADNA was preserved in response to MAP increase and HR responses to vagal efferent stimulation were augmented, we conclude that a deficit of the central mediation of baroreflex HR contributes to the overall attenuation of baroreflex sensitivity in OVE26 mice. The successful conduction of physiological experiments on the ADN in OVE26 mice may provide a foundation for the understanding of cellular and molecular mechanisms of diabetes-induced cardiac neuropathy.

Managing medical care for patients with diabetes mellitus requires a comprehensive approach that includes empowering the patient to be an active participant in the management of their disease as lifestyle management, in addition to medical therapy, is a crucial component in the care of the diabetic patient. The objective of this project was to determine if implementing diabetic care cards in a family medicine residency clinic would increase patient engagement with their care in the form of knowledge concerning A1C values and subjectively feeling in control of their diabetes. The initial phase of the project involved providing diabetic patients a brief anonymous survey concerning their A1C and asking if they felt in control of their diabetes; these surveys were collected for several months. The next phase consisted of an educational lecture during formal resident physician didactic time where diabetic guidelines were discussed, diabetic care cards were introduced, and the resident physicians were encouraged to utilize the cards with their diabetic patients. After several months of implementation of the diabetic care cards in the clinic, the same anonymous survey was repeated with diabetic patients. A total of 93 anonymous patient surveys were collected prior to formal resident physician education concerning diabetic care cards and a total of 40 anonymous surveys were collected after formal resident physician education. The data from the pre and post educational surveys were then reviewed and compared and data was analyzed. Overall, A1C values did not significantly differ between the pre- and post-survey groups. Although there was a slightly higher percentage of patients who reported knowing their A1C level after the diabetic card implementation, this was not statistically significant and there was not a statistically significant difference in the percentage of patients that felt in control of their diabetes between survey groups. It was found that higher A1c values were associated with patients feeling less in control of their diabetes. A limitation of this study was realized with the methodology; it is not known if every patient who completed a survey also directly encountered the diabetic care card. The study yielded some valuable insight into patient perspective of diabetes control. It was found that an A1C less than or equal to 7%, which is the A1C goal for most diabetic patients, did not necessarily correlate with diabetic patients feeling in control of their diabetes. It was felt that this indicated that there is room for improvement in patient education concerning A1C goal. It also revealed a need for further investigation of the factors that influence whether a patient feels they are in control of their diabetes.

The aim of this thesis is to investigate different methods of improving the glycaemic control of diabetic out-patients, within the scope of the author's training both as a therapeutic dietitian and as a teacher. Evidence is presented from the literature, which indicates that high-carbohydrate, high-fibre diets are of benefit in diabetes, that supplements of viscous fibre improve glycaemic control, and that education of the diabetic patient may help to achieve good diabetic control, provided that the patient also complies with all parameters of therapy. Three main studies have been undertaken: - (1) An educational project, to investigate the effect of a mass-education programme on compliance and control in diabetic out-patients. (2) An investigation of the effect of long-term high-fibre diets in diabetic out-patients. (3) A study of the use of guar gum in the diabetic diet. In Study 1, a large random sample of patients attending a diabetes outpatient clinic were tested by means of a detailed questionnaire, in order to assess their existing knowledge of the disease. A suitable education programme was then devised and patients were exposed to this in the clinic situation. Another sample of patients was then re-tested with the same questionnaire and statistical analysis was used to assess the effect of this programme on knowledge, compliance and control. Results indicate that, while patients' knowledge scores improved, there was no improvement in dietary compliance and also no significant change in the standard of diabetic control in the clinic population. In Study 2 we investigated the practical aspects of administering a high-fibre diet to diabetic out-patients in Cape Town, in the light of the reported benefits of diets containing large amounts of dietary fibre (OF) in the control of diabetes. Readily-available, low-cost foodstuffs with a high OF content, were incorporated into suitable, individualised high-fibre meal plans for 10 selected diabetic out-patients. Patients were closely monitored over a period of 9 months, for 3 months of which the high-fibre diet was prescribed. Various parameters of glycaemic control were recorded and analysed, and the patients' compliance to the new regimen was assessed. Only 3 patients approached the projected fibre intake, but significant negative correlations were found between the dietary fibre increments and both mean plasma glucose and mean serum triglyceride changes. These findings suggest that, were it not for poor dietary compliance, a high-fibre diet might result in significant improvement in diabetic control, and that education and motivation are of prime importance when making major changes to patients' eating habits. Study 3 investigates the use of guar gum, when incorporated into the diabetic diet in both short- and medium-term studies. This viscous fibre has been shown by workers overseas to be effective in lowering postprandial glycaemia. In this study a palatable vehicle for the gum, a digestive-type biscuit, was tested for its effect on glycaemic control when incorporated into the usual meal plans of diabetic out-patients, and also against an oral glucose load as a reference standard. It was found to be effective in reducing the post-prandial rise in blood glucose, and in improving glycaemic control, as shown by reduced fasting blood glucose values and decreased 24-hour urinary glucose excretion. The biscuit proved to be palatable and acceptable to patients, and the guar gum was effective in much smaller quantities than have previously been tested. It may therefore prove a valuable adjunct to diabetes therapy. Results of these studies indicate that compliance to therapeutic recommendations is the crux of achieving good diabetic control. Increased diabetic knowledge alone does not lead to improved diabetic control, and compliance to altered eating habits is difficult to achieve unless prior education and motivation has taken place. The simplest means of achieving better glycaemic control of diabetes appears to be the use of a supplement of viscous fibre, which will improve the glycaemic response to the patients' usual meals.

PURPOSE: Previous studies have reported an increased prevalence of ocular diseases in patients with obstructive sleep apnea. The purpose of this study was to examine the link between such ocular diseases as diabetic retinopathy, diabetic macular edema, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, non-arteritic anterior ischemic optic neuropathy, and glaucoma. METHODS: This meta-analysis was conducted through a search using PubMed, Web of Science, Scopus and EMBASE. We identified both retrospective and prospective studies. RESULTS: The final meta-analysis looked at 30 studies and 7 ocular diseases. The data showed a high prevalence of obstructive sleep apnea for diabetic retinopathy and diabetic macular edema patients. Data for glaucoma and non-arteritic anterior ischemic optic neuropathy patients did not show a statistical increase. There was not enough data for retinal vein occlusion, central serous chorioretinopathy and age-related macular degeneration to calculate statistical significance. CONCLUSION: These data suggests that patient populations with diabetic retinopathy and macular edema show increased rates of obstructive sleep apnea. Data suggest that hypoxia is an important part of the pathophysiology of diabetic retinopathy and diabetic macular edema. Because obstructive sleep apnea has been shown to affect the progression of the ocular diseases included in this study, ophthalmologists should screen for the presence of obstructive sleep apnea to better help their patients. / 2021-06-14T00:00:00Z

The increasing reliance on drugs from natural sources has led to the development of several drugs from traditional plants which are present in abundance in Southern Africa. With the rapid increase of incidence of type 2 diabetes in South Africa with potentially devastating effects on healthcare, the need for alternative therapeutics is a priority. In this study, Schkuhria pinnata (Lam.) Kuntze was investigated for its antidiabetic potential. Initial screening of two different solvent extracts of S. pinnata identified an aqueous extract that lowered blood glucose concentrations in a hyperglycaemic streptozotocin-induced diabetic rat. The classical bioassay approach was followed by using different solvents, drying processes and fractionation in order to produce the most active extract and attempt to isolate an active compound(s). An aqueous freeze dried extract was found to be the most active at stimulating glucose uptake activity in C2C12 and Chang cells. Fractionation of this extract in an attempt to identify the active compound yielded a novel crystalline compound 1 by NMR analysis. Screening for bioactivity of the extract and compound 1 using C2C12 muscle and Chang cells revealed that both extract and compound 1 were biologically active, however the activity of the aqueous extract was more significant overall. A butanone/pentane extract prepared for possible commercialization purposes was also shown to be active in vitro. To establish antidiabetic activity, the aqueous freeze dried extract, butanone/pentane extract and the enriched compound 1 fraction were tested in a streptozotocin (STZ) diabetic rat model showing hypoglycaemic effects for the aqueous freeze dried extract. Messenger RNA and protein studies on C2C12 muscle cells revealed that the aqueous freeze dried extract and compound 1 enhanced insulin receptor, GLUT-4, glycogen synthase, pyruvate kinase and pyruvate carboxylase expression, suggestive of an insulin mimetic mode of action, while the butanone/pentane extract enhanced adenosine monophosphate-activated kinase (AMPK) protein expression by a non-insulin dependent mechanism. A pharmacokinetic study (PK) established bioavailability of compound 1 following oral administration of the extracts, but not from the compound 1 enriched fraction. From this study, the traditional use of S. pinnata has been scientifically validated as having antidiabetic properties. In vitro and in vivo bioassays, confirmed that an aqueous freeze dried extract which was prepared as per the traditional method had the most promising antidiabetic iii activity. Compound 1 isolated from an active fraction was proven to be almost as effective as the parent extract in in vitro studies. This compound could therefore be the major active ingredient responsible for the uptake of glucose in cells and the hypoglycaemic activity in vivo. In this study, the antidiabetic activities together with the mechanism of action of S. pinnata extracts and compound 1 were elucidated. The highlight of the study was the identification of a bioactive novel chemical entity (NCE) compound 1 (identified as 2-(2-{[(2E)-4-hydroxy2-(hydroxymethyl)but-2-enoyl]oxy}-4,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2- enoic acid) isolated from an active fraction of S. pinnata that was proven to be almost as effective as the parent extract in in vitro studies. This compound could therefore be the major active ingredient responsible for the uptake of glucose in cells and the hypoglycaemic activity in vivo. The cellular mechanism of action of the S. pinnata extracts and compound 1 demonstrated both insulin mimetic and non-insulin dependent mechanisms (AMPK) in C2C12 muscle cells. Further research in the form of preclinical and clinical trials need to be undertaken to make this extract or biologically active compound available as a herbal remedy or nutraceutical therapeutic for diabetes. To achieve this; safety, efficacy and mode of action studies will have to be established. The synthesis of compound 1 and/or analogues should also be investigated as an antidiabetic drug candidate.

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