Pathophysiology of Diabetes

Assignment 2
Weighting: 60%
Requirements: Written assignment (3000 words)
Assignment topic

The aim of this case-study is to encourage you to explore the impact of the onset and course of diabetes complications, both macrovascular and microvascular.
Choose one (1) macrovascular AND one (1) microvascular complication situation from the following scenarios:
1. Macrovascular complications of diabetes:
a. A 60 year old person with type 1 or type 2 diabetes, who has had diabetes for more than 15 years, presents with hypertension.
b. A 42 year old person with type 1 or type 2 diabetes, who has had diabetes for more than 8 years, presents with dyslipidaemia.
c. A 64 year old person with type 1 or type 2 diabetes, who has had diabetes for more than 10 years, presents with atherosclerosis.

2. Microvascular complications of diabetes:

a. A 45 year old person with type 1 or type 2 diabetes, who has had diabetes for more than 12 years, is diagnosed with retinopathy.
b. A 55 year old person with type 1 or type 2 diabetes, who has had diabetes for more
than 15 years, is diagnosed with nephropathy.
c. A 62 year old person with type 1 or type 2 diabetes, who has had diabetes for morethan 10 years, is diagnosed with neuropathy.

? Outline the pathophysiological processes that cause macrovascualr and microvascular complications in people with diabetes at a cellular level.
? Explain the underlying pathophysiological principles in relation to both of the chosen complications, specifically:
• A brief discussion of the risk factors associated with these complications occurring in a person with diabetes
• Identify and briefly discuss the stages of development/progression of each complication chosen and the corresponding signs and symptoms
• Briefly discuss the diagnostic tests that might be used to diagnose and monitor the progress of both these complications
• Outline briefly the key evidence based management and/or treatment strategies recommended for each complication

Lecturer said
Remember this unit is all about pathophysiology, so you need to demonstrate that you understand the patho processes involved.
Outline may be like this
‘Explain the underlying pathophysiological principles in relation to both the chosen complications’ for each micro and macro complication
– ‘A brief discussion of the risk factors associated with these complications occurring in a person with diabetes’
– ‘Identify and briefly discuss the stages of development/progression of each complication chosen and the corresponding signs and symptoms’
-‘Briefly discuss the diagnostic tests that might be used to diagnose and monitor the progress of both these complications’
-‘Outline briefly the key evidence based management and/or treatment strategies recommended for each complication’
Below is my effort but it needs a lot of work still I feel. So I need it all redone but the information may be useful to you . keep in touch ask me about things if you are not sure please .
Introduction
The risk of developing either microvascular or macrovascular disease in the person with diabetes is dependent on both the duration of the disease and the severity of hyperglycemia. Many authors agree that uncontrolled hyperglycemia over time puts the person at a high risk of developing diabetes complications (Fowler 2008). Microvascular disease involves neuropathies that include sensory and motor and autonomic neuropathy. Mononeuropathy and radiculopathy, cranial and mononeuritis are called asymmetrical syndromes. When people are assessed for neuropathy they should be assessed for insensate neuropathy or lacking physical sensation. Macrovascular disease occurs in both type 1 and type 2 diabetes. In type two diabetes patients “often have coexisting disease” (Therapeutic guidelines. 2014 p. 67) such as elevated blood pressure or dyslipidemia, which can contribute to cardiovascular risks. Patients with type 1 diabetes are also at risk of complications and management of the complications can be both complex and should be managed by an endocrinologist (Therapeutic guidelines. 2014).

Microvascular Pathophysiology of Diabetic Neuropathy and Development progression
Diabetes neuropathy is a microvascular complication of diabetes. It occurs at distal axonal and when demyelination takes place and tries to begin nerve regeneration, at the base of thickening of the vasa nervorum and also in endothelial cells changes. The changes cause occlusions resulting in nerve conduction and functional damage within the cells Watkins, Amiel, Howell, Turner, (2008). Microvascular disease affects results in ischaemic and metabolic neuronal oxidation of nutritate generation within the cell leading to an activation of several pathways including the “polyol pathway, non-enzymatic glycation, and formation of advanced end products (AGES), activation of diacylcerol protein kinase C-B transcriptions factors and a mitogen activated protein kinase (MAPK) and the accumulation of reactive oxygen species (ROS)” (Bilous, Rudy, Donnelly, Richard. 2010 p 130).
The classifications of diabetic neuropathies are focal, which is mononeuritis or by entrapment and occurs in a single nerve, sensory neuropathy, autonomic, mononeuropathy and proximal motor neuropathy which are also called amyotrophy. The cause of neuropathy is thought to be related to several processes including aldone reductase, which is the first enzyme in the polyol pathway and an increased oxidative stress related to sorbitol accumulation, hyperglycemia and overloading of glucose metabolism, which results in an increased use of the polyol pathway. Fowler, 2008 and (Shaw, Cummings, 2012). It is this access in hyperglycemia that “leads to an access in activity of the enzymes aldose reductase and sorbitol dehydrogenase” Clayton, Esley (2009 p2). This results in the conversion of intracellular glucose to methylgoyxal and acteol also to sorbitol and fructose. In neuropathy there is also decreased nitric oxide and impaired sodium and potassium (NA+K+) and (AT-pase) stores. The action of this actinic conversion of glucose after-effects results in an increase of nicotinamide adenine dinucleotide phosphate and hydrogen Clayton, Elasy (2009). This conversion accumulates and causes hypersensitivity. It also contributes the discharge of ectopic electrical impulses causing pain. This pathway leads to decreased levels of myoinosital and glutathione which in turn increases the levels of free radical damage and lower levels of nitric acid Bowering (2001). It is this process that is obligatory for the detoxification of reactive oxygen species and for the synthesis of the vasodilator nitric oxide (Clayton, Esley 2009). Eventually the aberrant glycation of nerve cell proteins and the incongruous activation of protein kinase C, results in further nerve dysfunction and therefore leading to ischemia of the nerves and to vascular system changes (Shaw, Cummings, 2012).

It is this sensorimotor polyneuropathy that leads to complications in the feet. Patients may experience tingling, burning, and alydonia. This can also lead to ulceration of the feet. Fowler, 2008 states “an absence of peripheral sensation is > 87% sensitive in detecting the presence of neuropathy” p 79, Neuropathic pain rises from central and peripheral origins, mainly via peripheral nerve fibers, small delta and C-nerve fibers.” hyperexcitable peripheral nerve fibers lead to hyperexcited central fibers through the stimulation of the postsynaptic N-methyl-D-aspartate receptors” (Tavakoli, Mojaddidi, Fadavi , Malik 2008 p194). However in a person with diabetes the sources of pain may be both central and peripheral and affect the entire body.

The central mechanisms of diabetic neuropathy DAG – diacylglycerol and low density lipoprotein include centralisation, reduced descending inhibition and A_B fibres release in the dorsal horn (Tavakoli et.al. 2008). Peripheral mechanisms sensitisation, transmutations in sodium channels, vicissitudes in neuropeptide expression, axonal atrophy , glycemic flux , damage to nerve fibers C and Ao and sympathetic sprouting, leading to altered blood flow. It is with this process that any impaired regeneration may release inappropriate excitation pulses which the patient may perceive as pain and parasthesiae. This can lead to sensory loss in the limbs. The vascular insufficiency leads to the patient experiencing a decreased threshold of cold tolerance. “Damaged peripheral nerves become epinephrine-sensitive and result in sympathetically mediated pain Patients may also have selective sympathetic denervation in their feet evidenced by increased norepinephrine” (Tavakoli, Mojaddidi, Fadavi , Malik 2008 p194).
The trauma and entrapment of the nerve can lead to structural nerve damage. The process can include segmental demyelination, axonal atrophy or loss, and progressive demyelination (Zimmerman, 2014)
Numerous patient first indication of neuropathy incorporate calf ache and hyperalgesia, squandering of the feet may happen. It is this harm to the innervations of the inborn foot muscles that prompts awkwardness between flexion and growth of the influenced foot. This produces anatomic foot disfigurements that make strange hard prominences and weight focuses, which step by step reason skin breakdown and ulceration (Clayton, Esley 2009)
Signs and manifestations of neuropathy rely on upon the kind of neuropathy. Most normally patients create symptomatic distal polyneuropathy. Signs incorporate sadness or misfortune of lower leg jerks and vibratory sensation, with hyperalgesia and calf torment in a few patients. The setback is in a stocking-and-glove dissemination. Squandering of the little muscles of hands and feet can likewise happen.
Autonomic neuropathy prompts a lessening in sweat and oil organ practicality. Thus, the foot loses its regular capacity to saturate the overlying skin and gets dry and progressively helpless to tears furthermore the ensuing advancement of disease. The misfortune of sensation as a piece of fringe neuropathy fuels the advancement of ulcerations. As trauma happens at the influenced site, patients are regularly unable to distinguish the affront to their easier furthest points. Thus, numerous wounds go unnoticed and dynamically exacerbate as the influenced range is consistently subjected to monotonous weight and shear powers from ambulation and weight bearing (Clayton, Esley, 2009)
The DCCT discovered some change in neuropathy with serious diabetes control. On the off chance that this is not fruitful, further medicine of neuropathy is revolved around agony control. The most widely recognized neuropathy is two-sided distal polyneuropathy. Expanding quantifications of tricyclic antidepressants, neurontin, dilantin, tegretol, and benzodiazepines have been utilized with shifting degrees of achievement. Gastroparesis is treated with metoclopramide (Zimmerman, 2014)
Autonomic neuropathy causes noteworthy dreariness and on occasion horribleness. Brokenness in organs can show as gastroporesis, blockage, diahorrea , erectile dysfunction , bladder, dysfunction, resting hypertension and quiet ischemia . The noiseless ischemia is connected with cardiovascular dysfunction and an expanded danger of ischemia and mortality (Tavakoli et.al. 2008)
Diagnostic tests
Standard tests include conduction studies and vibration perception thresholds (VPTs) Any pain in the feet is generated and medicated C and A- d fibers. Vibration and sensory testing focuses on the large nerve fibers and cold perception is assessed (A- d fibers) and warm sensation by (C fibers) (Tavakoli et.al. 2008)

Evidenced based management and treatment strategies
Intensive blood glucose control first-line tricyclic antidepressants (TCAs; amitriptyline), second-line anticonvulsants (gabapentin), carbamazepine and phenytoin could also be considered and third-line opioid-related treatment. Duloxetine is also considered as beneficial in treating and opioid related treatment is also suggested as treatment (Bowering 2001)

Podiatry for foot and vascular assessment and education on correct foot ware choices and an accurate foot measurement should be performed before purchasing new shoes.
Peripheral neuropathy reduces awareness of foot problems that may be caused by footwear choices and other foreign bodies. The feet should be assessed with a 10 g monofilament and a tuning fork; 128 Hertz for vibration threshold are used in assessing neuropathy. Any changes noticed suggest foot problems (Bowering, 2001)
Autonomic neuropathy can also cause anhidrosis or drying of the skin. Motor neuropathy, alters foot muscle tone, leading to clawing of the toes, this in turn puts pressure on the ball of the foot, and predisposes the patient to callus and ulcer formation. The presence of other microvascular complications such as nephropathy, and retinopathy are suggested risk factors foot ulcer development. Any previous ulceration requires closer monitoring for foot problems (Clayton, Esley, 2009)

Macrovascular Pathophysiology of Dyslipidemia and Development progression
Dyslipidemia is aberrant levels of lipids with the blood characteristic of type 2 diabetes. People with type 2 diabetes have various types of dyslipidemia with significant risk factors of cardiovascular disease in patients with metabolic syndromes (Ascher, Ruiz, 2012) Insulin resistance is accepted to assume a pivotal role in altered metabolism of triglyceride lipoproteins and the development of dyslipidemia. Conformation from epidemiological studies proposes the link between insulin resistance and insulin tolerance.
The digestive tract absorbs consumable fat and bundles it into chylomicrons, which is then transported to peripheral tissues through the blood. (Haffner Lehto, Rönnemaa, Pyörälä, Laakso 1998 ). Dyslipidemia is an issue of elevated or abherrant levels of lipids and/or lipoproteins in the blood. Low-density lipoproteins (LDL); back cholesterol from the Live to cells within the body. LDL has an allotment in initiating atherosclerosis. This is the way dyslipidemia becomes a accident risk for atherosclerosis and consequently cardiovascular diseases. The enzyme lipoprotein lipase breaks down chylomicrons; and acids enter muscle and adipose tissues. The chylomicron remnants are after taken up by the live to alpha the action of very-low-density lipoproteins (VLDLs) synthesis.

After the amalgam of Apolipoprotein (APO) B100, that is an capital basic of VLDL. The liver secretes VLDL which undergoes lipolysis by lipoprotein lipase to form LDLs. LDLs are again taken up by the liver and by the peripheral tissues. HDL is produced by the liver. Its action is to carriage cholesterol from the anatomy aback to the liver.
The chemical lipoprotein lipase breaks down chylomicrons; and unsaturated fats access muscle and fat tissues. The chylomicron assortment is appropriately captivated by the liver to activate the action of low-thickness lipoproteins (Vldls) union. After the blending of Apolipoprotein (APO) B100, that is a fundamental allotment of VLDL. The liver secretes VLDL which adventures lipolysis by lipoprotein lipase to anatomy Ldls (Atef 2013) Ldls are then captivated by the liver and by the binding tissues. HDL is adapted by the liver. Its accommodation is to carriage cholesterol from the anatomy afresh to the liver. Dyslipidemia is insulin subordinate catalysts, for example, lipoprotein lipase and brings about a deferred systemic leeway of specific lipids. This is an insufficiency of apolipoprotein C-II lack. This atom is utilized within the coupling methodology of lipoprotein lipase (LDL) to its receptor to move the cholesterol to the tissues. (Atef 2013) Dyslipidemia is a high plasma amassing of triglycerides and low centralization of high thickness lipids and an expanded convergance of low thickness lipids Hachem, Mooradian, (2006). This is an APOE defect mediated by the re uptake of cholesterol and triglycerides by the liver there is an incrementation VLDL, and incremented IDL and withal incremented chylomicrons. (Atef, 2013)
The principle cardinal characteristic of diabetic dyslipidemia is an increment in unsaturated fat discharge from insulin safe fat cells. This is an abandon that includes apolipoprotein B100 levels to expand and LDL receptor tying reductions. With the goal that coupling does not happen. There is likewise an increment in the LDL and VLDL. It is consequently that dyslipidemia is recognized to help atherosclerosis or solidifying of the supply routes. Changes incorporate both expanded hepatic emission of VLDL and disabled freedom of VLDL and intestinally determined chylomicrons. A vital result of impeded freedom is delayed plasma maintenance of both VLDL and postprandial chylomicrons as mostly lipolyzed leftover particles. (Bluher Kratzsch, Paschke, 2001).
Dyslipidemia is insulin dependent enzymes such as lipoprotein lipase and results in a delayed systemic clearance of certain lipids. This is a deficiency of apolipoprotein C-II deficiency. This molecule is utilized in the binding process of lipoprotein lipase (LDL) to its receptor to move the cholesterol to the tissues.
After the synthesis of Apolipoprotein (APOE) B100, that is an essential component of VLDL. There is an APOE imperfection interceded by the re uptake of cholesterol and triglycerides by the liver there is an increased increment in VLDL, levels and expanded IDL levels and additionally an increase in chylomicrons. Insulin safety and Type 2 diabetes, expanded efflux of free unsaturated fats from fat tissue and weakened insulin-intervened skeletal muscle uptake of free unsaturated fats increment unsaturated fat flux to the liver (Bluher Kratzsch, Paschke, 2001). The way that free unsaturated fat levels are elevated in people with hindered glucose tolerance proposes that insulin safety that is connected with raised free unsaturated fat levels happens before the onset of hyperglycemia. In dyslipidaemia it is the receptor abandons on the hepatocytes, inside the liver that leads the to the LDL atoms and cholesterol being conveyed to tissues (Krauss, 2004)
Dyslipidemia is a high plasma concentration of triglycerides and low concentration of high density lipids and an incremented concentration of low density lipids (Mooradian, 2006). The main cardinal feature of diabetic lipidemia is an incrementation in adipose acid release from insulin resistant fat cells. This is a defect that involves apolipoprotein B100 levels to increment and LDL receptor binding decreases. So that binding does not occur. There is additionally an incrementation in the LDL and VLDL. It is for this reason that dyslipidemia is considered to contribute to atherosclerosis or hardening of the arteries.
Circulating cholesterol hails from two sources, de novo synthesis in the liver including the HMG COA reductase and intestinal assimilation of dietary and gut acids cholesterol. Combined with altered hepatic engenderment of apoprotein –B containing lipoproteins, usual findings include lipid abnormalities in VLDL. This expanded triglyceride levels holds chylomicrons and very low density lipids, and decremented high calibers density lipids cholesterol (Klein, R Klein S, Moss 1996)
“Patient’s with diabetes tend to have a higher proportion of smaller and denser LDL particles, which are more susceptible to oxidation and may thereby increase the risk of cardiovascular events”. American Diabetes Association
Insulin attrition and Type2 diabetes are affiliated with a absorption of commutual plasma lipids and lipoprotein irregularities, which absorb lessened HDL cholesterol, a arete of little array LDL particles, and elevated triglyceride levels.. Each of these dyslipidemia characteristics is connected with an expanded risk of cardiovascular disease. (Klein, R Klein S, Moss 1996) Expanded hepatic discharge of vast triglyceride-rich VLDL and disabled freedom of VLDL has all the earmarks of being of focal significance in the pathophysiology of this dyslipidemia. (Atef 2013) Little thick LDL particles appear from the intravascular advancing of accurate bigger VLDL forerunners. Ordinarily, diminished plasma HDL levels in sort 2 diabetes are showed as diminishments in the Hdl2b subspecies and relative or total builds in more diminutive denser Hdl3b and Hdl3c (Bluher Kratzsch, Paschke 2001). Because of this, small thickness LDL is recognized by numerous to be one of the signs of diabetic dyslipidemia as opposed to the normal sidekick of decreased HDL and expanded triglyceride levels. (Krauss2004).
The arrival of stored unsaturated fats from adipocytes obliges change of stored triglyceride into unsaturated fats and monoglycerides that could be exchanged over the plasma film of the cell. The essential protein that is answerable for this is hormone-sensitive lipase (HSSL). HSSL is repressed by insulin, which diminishes phosphorylation of HSSL and its acquaintanceship with the put away lipid droplet Bluher Kratzsch, Paschke (2001). Abatement in the size and an expansion in thickness of LDL are normal for most hypertriglyceridemic states, including diabetes. Bluher Kratzsch, Paschke (2001)

Risks
Common primary causes, are familial in nature, hypercholestremia , screening for other causes may include hyper thyroidism and or drug induced causes such as alcohol, thiazides and beta blockers.

Evidence Based Management and treatment strategies
Examinations incorporate a full history, dipstick of pee to test for protein. The accompanying Blood tests ought to be requested Urea, Electrolytes, creatinine and creatinine leeway and fasting lipids.
An ECG may be performed to evaluate for left ventricular hypertrophy. It likewise gives a pictorial presentation of the depolarisation and repolarisation of atrial and ventricular cells that might be surveyed by auditing number of waves and the interims. It is viewed as the highest level for evaluating heart status with negligible obtrusiveness. It is a fundamental demonstrative instrument for giving prompt and significant information essential for expedious conclusion and administration (Lee, 2007) and a midsection radiograph for cardiomegaly might additionally be requested. My reasons are that dichotomous tests have just 2 conceivable outcomes that is either a yes or a no, or a positive or negative. Basic dichotomous tests are x-beams, which are either typical or show an anomaly. A cortisol and dexamethasone suppressive test, catecholamine and renin aldosterone is different tests that may be requested.
Proven based interventions of dyslipidemia include medication systems, lifestyle progressions, weight diminishment and expanded physical movement. Decisions for treatment must be customised to the individual. A statin is considered the first line targeted treatment for raised cholesterol levels and that is above 4.0mmo/l and LDL is above 2.0 mmo/l.
There are four classes of lipid-bringing down medications: the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Coa) reductase inhibitors (the “statins”), including; atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. (Gore, Dukes, Rowbotham, Leslie, Tai, 2007) Then there are the fibrates (gemfibrozil and fenofibrate), niacin/nicotinic corrosive, and the bile corrosive tying gums (colestipol, colesevelam, and cholestyramine). Other drugs include the cholesterol assimilation inhibitor, Ezetimibe, and Omega-3 unsaturated fats. (Atef 2013)
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