There is ample evidence available for the link between type 2 diabetes, obesity, hypertension, renal disease and comorbid conditions of these disease conditions are well researched. People with obesity are 2.3 billion and type 2 diabetes are 365 million (Kawano and Arora, 2009). Particularly, in the older age people, there is the occurrence of chronic comorbid conditions of the above mentioned disease conditions rather than the occurrence of the individual disease. These comorbid diseases are more serious health issues and it is difficult to control these conditions. In this report, a patient with the occurrence of comorbid conditions of type 2 diabetes, overweight, hypertension, renal dysfunction, retinopathy and oedema is presented. The question here is how would a person develops different disease conditions? Is there any connecting link among these comorbid disease conditions? Pathophysiology of each of these conditions is being described and different pathways and biomarkers connecting these disease conditions are being mentioned. Also evidence for the occurrence of these comorbid conditions is described.
Type 2 Diabetes:
This patient is diagnosed with type 2 diabetes. Type 2 diabetes mellitus is the most common form of diabetes i.e. increases in sugar level in the body. Fasting glucose level should be below 140 mg/dl and random blood glucose level should be below 180 mg/dl. Type 2 diabetes occurs either due to the resistance to the action of insulin or insufficient secretion of insulin from the beta cells of the islets of Langerhans. This insulin resistance, mainly occurs in the liver, skeletal muscle and adipose tissue. Binding of insulin to its receptor results in the tissue specific actions such as inhibition of glucose production by liver, promotion of glucose uptake by skeletal muscle and inhibition of lipolysis in adipose tissue. In case of insulin resistance, there is the disturbance in the suppression of glucose production by liver, clearance of glucose by the liver and promotion of lipolysis by adipose tissue (Olefsky and Glass, 2010). In type 2 diabetes, beta cells become dysfunctional and there is no control of hyperglycaemia. Free fatty acids also induces, insulin resistance specifically in muscle by disturbing insulin signalling pathway. One of the intermediate products of triglyceride metabolism, diacylglycerol activates protein kinase C, which phosphorylate serine and threonine residues located at the insulin receptor and insulin receptor substrate, which results in the insulin resistance. Incretins are metabolic hormones, which stimulate insulin release and inhibit glucagon release. Hence, deficiency of incretins leads to the type 2 diabetes. Glucagon is a peptide hormone secreted by the alpha cells of the pancreas and it increases the glucose level by gluconeogenesis (glucose synthesis by liver and kidney) and glycogenolysis (breakdown of glycogen in glucose). Type 2 diabetes mellitus affects different body organs and their respective systems. It procures dyslipidaemia and hypertension. In case of dyslipidaemia, there is the increase in cholesterol (~60 %), low density lipoprotein (LDL)-cholesterol (~41 %) and triglycerides (~51%) of the total cases. In another study, it has been quoted that about 65 % people have increased triglyceride and decreased high density lipoprotein (HDL) (Mayer-Davis et al., 2009; Tryggestad and Willi, 2015).
Type 2 Diabetes and Renal Complication Comorbidity:
With this mentioned patient, there is the renal complication due to the type 2 diabetes. In the previous studies, it is evident that around 18-72 % type 2 diabetes patients developed nephropathy in the form of microalbuminuria and abnormal albumin to creatinine ratio (Tryggestad and Willi, 2015). Elevated levels of protein and glucose in the urine reflect proteinuria and diabetes, respectively and both these conditions leads to the renal failure. This proteinuria is associated with obesity and diabetes. In these type 2 diabetes patients there is the increase in the renal plasma flow and 25-50 % increase in the glomerular filtration rate. Increased reabsorption of the glucose and sodium in the proximal tubule is responsible for the increased glomerular filtration rate (Helal et al., 2012; Vallon, and Thomson, 2012). Hyperglycaemia also begins formation of advanced glycation end products (AGEs), increased expression of AGE receptor (RAGE), activation of polyol, hexosamine pathways and activation of protein kinase C (pkc) pathway. Oxidative stress in the mitochondria leads to the production of inflammatory cytokines like Interleukin-1 (IL-1), IL-6 and Tumor necrosis factor alpha (TNF-?) and profibrotic growth factors like Transforming growth factor (TGF) and Vascular endothelial growth factor (VEGF). All these factors lead to the renal injury (Navarro-Gonz?lez et al., 2011; Muskiet et al., 2014).
This complex health condition affects patient and his family very seriously. Three can be possibility that patient can feel social withdrawal. That can be due to the frequent urination due to the renal complication in the patient. Also, patient loses his freedom on the food to be consumed due to diabetes. This also makes patient family low, however patient family should try to uplift patient moral.
It is observed that mentioned patient is overweight. In overweight patient body mass index (BMI) should be between 25-30. Overweight condition results due to the imbalance in the energy intake and expenditure. There is the increase in the adipose tissue in the overweight people. There is the increase in the level of leptin, TNF-alpha, IL-6, angiotensin, plasminogen activator inhibitor and resistin in the overweight people. On the other hand, there is a decrease level of adiponectin in overweight people. Leptin is produced by the adipose tissue and considered as the satiety factor which gives signals of excess fat reserve in the body and bring about appetite control. However, most of the overweight people are leptin resistant. Along with the function as energy reservoir, adipose tissue also secrets adipokines like cytokines, hormones, growth factors, acute phase proteins, prostaglandins, glucocorticoids and sex steroids. In overweight people macrophages are permeated into the adipose tissue and consequently shift from macrophage M2 to macrophage M1 occurs. These hypertrophied adipose tissue along with M1 secrets proinflammatory cytokines like TNF-alpha and IL-6 (Maury and Brichard , 2010 ; Schmidt et al., 2015). Renin-angiotensin system in adipose tissue is an important connects for the association of obesity and hypertension. Angiotensin II plays a role in adipose tissue growth and differentiation (Mehri et al., 2010; Kalupahana and Moustaid-Moussa, 2012). Adiponectin is a collagen-like protein secreted by adipose tissues. Adiponectin induces energy expenditure. As there is less secretion of adiponectin in overweight people, energy expenditure is less.
In mentioned patient there is the comorbid condition of overweight and type 2 diabetes. Occurrence of type 2 diabetes is more in the overweight people as compared to the type 1 diabetes. It is found that around 30 % overweight people are susceptible to the development of type 2 diabetes (Wang et al., 2015). Due to increase in the free fatty acids in the overweight patients, there is the decompensation of insulin producing beta cells and insulin resistance. These fatty acids get oxidised and produces reactive oxygen species, which activates IKK?, NFk?, TNF? and JNK pathway. This JNK phosphorylate insulin receptor and produces decreased insulin signalling and insulin resistance.
Overweight and Hypertension Comorbid Condition:
Along with the overweight condition and type 2 diabetes, there is the elevated blood pressure in the mentioned patient. Around 25 % overweight people developed hypertension as compared to the normal people (Luo et al., 2013). Overweight people are associated with increased blood flow and hypertension. Increased leptin in the overweight people also produces hypertension through sympathetic activation. There is the increased renin activity in the overweight people, which activates renin-angiotensin system and results in the hypertension through sympathetic activation. Also there is the increased secretion of insulin in the overweight people, this insulin also stimulate renal reabsorption of sodium and leads to the hypertension (Richard., 2009). In overweight people renal dysfunction is more as compared to the normal people (Franchini et al., 2015). Increased level of the leptin in the obesity is responsible for the proteinuria. In overweight people, adipocytes exert inflammatory and endocrine function and produces vascular damage in the kidneys. Hence, there is the increased hyperfiltration and glomerular filtration rate (GFR), albumin excretion rate (AER) and microalbuminuria (Sanad and Gharib, 2011). In overweight people adipose tissue releases leptin, this stimulates aldosterone release from adrenal gland which is responsible for sodium retention and hypertension.
Due to overweight and hypertension comorbid condition, patient cannot do more physical activity and cannot tolerate more stress. Patient may feel isolated in the social life. Due to this inactive state of patient, one of the family members should always be with the patient to take care of him. In this case family members cannot concentrate on their personal and professional work. This affects social and financial status of the family.
Diabetic retinopathy, which is caused due to the increased retinal vascular permeability resulted in the vascular proliferation and vision loss. Diabetic retinopathy occurs in around 40-60 % patients with non-existing retinopathy and progression of retinopathy in around 30 % patients with existing retinopathy (Mayer-Davis et al., 2012).
Normal blood pressure range is 100-140 mmHg systolic and 60-90 mmHg diastolic. Hypertension is considered if blood pressure is consistently above 140 mmHg systolic and 90 mmHg diastolic (Mancia et al., 2013). In hypertension, there is the increased resistance to blood flow i.e. increased peripheral resistance due to the narrowing of the small arteries and arterioles and also due to the less number of capillaries. Reduced peripheral venous compliance also plays role in hypertension, which causes venous return, elevate cardiac preload and finally results in the diastolic dysfunction. Main mechanisms involved in the hypertension are dysfunctional renin-angiotensin system, atypical sympathetic nervous system, insulin resistance, endothelial dysfunction and vascular inflammation. Renin stimulates adrenal gland to secret more aldosterone through renin–angiotensin–aldosterone system (RAAS), which induces sodium retention, which is responsible for hypertension. The sympathetic nervous system also acts through the same pathway by activating the RAAS system in the kidney. Excessive oxidative stress and vascular inflammation are responsible for the hypertension in the endothelial dysfunction. There is the increased activity of oxidative stress marker i.e. nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the hypertension (Dharmashankar and Widlansky, 2013). There is the increased production of inflammatory cytokines like Interleukin-17 (IL-17), IL-1, IL-6, IL-8 and TNF? in the hypertensive patients. (Gooch and Sharma, 2013). Hypertension has been reported to be in the range of 30-65 % patients with type 2 diabetes (Mayer-Davis et al., 2009; Ruhayel et al., 2010).
Ankle swelling is associated with loss of protein in the urine, which indicates renal failure, which is again due to the diabetes, hypertension and obesity. Due to the loss of protein in the urine, there is lower protein level in the blood of the patient, which leads to the ankle swelling. Due to hypoalbuminea there is the low capillary colloid oncotic pressure, which leads to the transfer of fluid from the vascular system to the interstitial fluid compartment and decreased circulatory volume. As a result, there is the compensatory renal sodium and water reabsorption, which leads to the development of oedema. Also kidney failure leads to the accumulation of fluid in the ankle region, which leads to the ankle swelling (Ellis, 2016).
Metformin is the first line treatment for the type 2 diabetes. Mentioned patient is consuming 500 mg BD metformin. Main action of metformin is through AMP-activated protein kinase (AMPK) activation, which prevents CREB–CBP–CRTC2 complex formation, resulting in the inhibition of gene transcription for gluconeogenesis. Along with hepatic glucose synthesis, metformin also enhances peripheral glucose uptake through the phosphorylation of Glucose transporter type 4 (GLUT4) (Pryor and Cabreiro, 2015). In addition to the type 2 diabetes, metformin is proved to be effective in the albuminuria in patients with diabetes mellitus which is one of the complications of the mentioned patient (Nasri and Rafieian-Kopaei, 2014). In previous studies, it has been shown that metformin is effective in weight reduction, however results from these studies were inconsistent (Park et al., 2009).
This patient has type 2 diabetes since last 15 years, however it has not been taken care properly. Due to sustained high level of glucose this leads to the different conditions like hypertension, renal failure, blurred vision and oedema. Since, this patient worked as an accountant there is not much physical activity and moreover, there is less control over the diet and sedentary lifestyle, this patient became overweight over the time period. This overweight condition and along with the type 2 diabetes leads to different cardiovascular complications, nephropathy and retinopathy. Due to all these diseases, patient health condition becomes very complex and in this condition patient care should be done using an interdisciplinary team of respective departments. Along with medication, care should be provided to the patient in terms of diet, lifestyle changes and exercise. Because these conditions can be controlled by implementing all these strategies.
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