Diabetes complications Flashcards
Recognize acute complications of diabetes including diabetic ketoacidosis and hypoglycemia.
(DKA) result of severe insulin deficiency and increase in counter regulatory hormones leading to extreme hyperglycemia. The low insulin:glucagon ratio promotes delivery of amino acids and fatty acids to the liver, for gluconeogenesis and to be converted to ketones respectively. Increased intrahepatic glucagon and epinephrine cause an increase in carnitine acetyltransferase (CAT) activity and a decrease in malonyl CoA activity which together allow fatty acids to enter the mitochondria. In the mitochondria, fatty acids are converted into ketone bodies. Since insulin is low, there is both increased production in glucose and ketones and decreased utilization of both. In order to reverse DKA, the changes to CAT and malonyl CoA regulation must be returned to normal. DKA presents with altered mental status or coma as well as signs of dehydration including loss of skin turgor, hypotension and weakness. Postural hypotension and tachycardia are the most common symptoms. Treatment of DKA is volume replacement and insulin, as insulin will inhibit gluconeogenesis and ketogenesis.
Hypoglycemia is the most common acute complication of diabetes. Symptoms of hypoglycemia appear when glucose falls to 50 or 60 (but can vary) and are divided into 2 categories which are due to CNS dysfunction (from lack of useable glucose) or excessive sympathetic secretion of epinephrine: Adrenergic (Sympathtic secretion) Sweating Tremor Tachycardia Anxiety Hunger
Neuroglycopenic (CNS) Confusion Dizziness Headache Decreased mental activity Clouding of vision Convulsions Loss of consciousness
Hypoglycemia is the limiting factor in aggressive blood glucose control with insulins. It is far more common in Type 1 than Type 2. Recovery from hypoglycemia is due to glucagon and epinephrine, because both stimulate glycogenolysis in the liver and release of glucose. However, after a variable duration of disease, glucagon responsiveness is lost and epinephrine release is blunted resulting in the loss of the 2 major corrective mechanisms. Hypoglycemic Unawareness happens when the patient no longer perceives the adrenergic warning signs of hypoglycemia. These patients can devolve rapidly and is more common in patients with frequent episodes of hypoglycemia. The only treatment for this is to avoid hypoglycemia for at least 3 weeks.
- Describe the mechanisms underlying the excess macro-vascular complications in diabetes and therapeutic interventions.
Diabetes is an independent risk factor for CVD including MI, stroke and PVD. HTN is a major contributing factor to both microvascular and macrovascular complications. Additionally, hyperinsulinemia (often part of T2DM) is associated with metabolic syndrome. Insulin resistance leads to increased triglycerides produced by the liver, which in turn decreases HDL (HDL shuttles triglycerides out of the body). All of these mechanisms result in changes to vasculature walls.
Normal endothelium has several properties: endothelial cells are anti-adherent, tight junctions prevent things from dissecting under the epithelium, they make NO, a vasodilator and they make TPA as well as anticoagulant factors. Hyperglycemia causes tight junctions between endothelial cells to become looser, which allows LDL to get under the endothelium. Macrophages attack the free LDL in the subendothelium and become foamy macrophages. This produces inflammation which leads to cytokine release. Cytokines cause local vasoconstriction, attract more macrophages to potentiate the inflammatory response and attract platelets so a clot will begin developing. The increased platelet response causes a pro-coagulant response and the damaged endothelium produces less tPA to break down fibrin clots.
The interventions to prevent these complications are basically the same as the interventions provided to non-diabetic patients with cardiovascular risks. β-blockers, antihypertensives and lipid lowering agents should be prescribed to diabetic patients who need them. Early intensive glycemic control may decrease the rates of macrovascular events later.
- Describe the mechanisms by which hyperglycemia causes the development of micro-vascular diabetic complications.
Polyol Pathway
Hyperglycemia causes increased flux of glucose into cells
Aldose reductase can convert glucose into sorbitol and fructose which cause osmotic and oxidative stress
Increased stress cause abnormal cellular function
Aldose reductase is expressed prominently in the eye, contributing to retinopathy
Non-enzymatic glycosylation
Hyperglycemia causes binding of glucose to amine groups on proteins and nucleic acids which eventually form advanced glycosylation end products (AGEs)
AGEs disrupt the basement membrane
In vasculature, AGEs cause decreased NO secretion, thus impair vasodilation
AGEs bind receptors which cause production of type IV collagen in renal mesangial cells (if you recall from back in May, too much collagen in glomeruli = bad times), expression of adhesion molecules on endothelial cells (also bad…woo hypercoagulability) and production of VEGF and other growth factors
AGEs can crosslink DNA, disrupting DNA function and repair
Elevation of protein kinase C
Hyperglycemia causes increased activation of protein kinase C (PKC)
In renal and vascular cells, this increased activity of PKC causes production of collagen and fibronectin resulting in basement membrane thickening
In endothelial cells, PCK causes more expression adhesion molecules (ICAMs), PAI-1 and VEGF with decreased NO production
Oxidative/carbonyl stress
As glucose builds up intracellularly it can uncouple mitochondria, which leads to production of reactant oxygen species
Oxidant injury causes enzymatic blockade of glycolysis, resulting in shunting of glucose into deleterious pathways mentioned above
- Identify the micro-vascular complications of diabetes.
Retinopathy
Diabetes is the leading cause of blindness in the US, and it is a largely preventable progression from retinopathy. Pericytes are the neurons of the eye that regulate blood flow. Hyperglycemia is toxic to pericytes and high levels of glucose cause pericyte drop out. Loss of pericyte function causes loss of autoregulation of blood flow which results in capillary drop out, basement membrane thickening and leakage of intravascular fluids into the eye (hard and soft exudates). This abnormal blood flow causes a hypoxic state within portions of the eye, which stimulates local release of VEGF and cytokines. VEGF stimulates angiogenesis in the retina and it is the development of these new vessels that results in blindness.
Neuropathy
This is a common complication of diabetes. The neurotoxic environment in diabetes is complex and includes hyperglycemia, hyperosmolarity, increased production of polyols, effects of AGEs, oxidant stress, hypoxia, development of neural antibodies and loss of neurotrophins. Pathogenesis of neuropathies involves neuronal attempts to survive, regenerate and maintain function in this environment. There are several types of neuropathy that affect patients with diabetes:
Distal Symmetric polyneuropathy
Stocking-glove distribution
Painless or painful
Deep, gnawing pain delta fibers
Superficial pain/parasthesias C fibers
More common in tall men, due to length of nerves
Usually starts in feet
Autonomic neuropathy-
Associated with increased risk of cardiovascular death
Chronic tachycardia
Orthostatic hypotension/inappropriate heart rate response
Gastroparesis and constipation
Sexual dysfunction
Hypoglycemic unawareness
Mononeuritis multiplex
Ischemic event due to vascular occlusion effects only a single nerve distribution
Recovers
Diabetic amyotrophy
Severe neuromuscular wasting syndrome
There is often improvement over the course of years (usually incomplete)
Nephropathy
Diabetes is also the leading cause of renal failure and dialysis in the US. Hyperglycemia causes hyperfiltration because the osmotic load is greater. Intrarenal and peripheral hypertension develop, although at this stage the GFR still appears normal. The injury progresses to basement membrane thickening of the glomeruli, mesangial proliferation and eventual destruction of the glomerulus. One of the earliest signs of nephropathy is microalbuminuria. Overt proteinuria is a critical marker of impending renal disease, and without treatment, GFR decline is rapid.
Diabetic Foot Disease
Impaired blood flow and sensation in the extremities leads to increased rates of mechanical trauma and infectious complications. For example, hammer toes can develop from contractures, leading to improper weight bearing and development of ulcers on the foot. The ulcers can then become infected and the immune system cannot clear the infection. This can lead to hospitalization and amputations.
- List treatment approaches that have been shown to be useful in preventing complications from diabetes.
Retinopathy
Blindness can be prevented by regular ophthalmic monitoring in patients with retinopathy. Once the eye reaches the severe pre-proliferative stage or early proliferative stage photocoagulation can be used. Tight glycemic control can prevent or delay onset of retinopathy. First line therapy is photocoagulation or intravitreal pharmacotherapy +/- photocoagulation. For persistent or recurrent disease, photocoagulate again and intravitreal triamcinolone acetonide or anti-VEGF therapy. For refractory disease consider a pars plana vitrectomy (where entire vitreous humor is removed).
Neuropathy
Not specifically addressed…glycemic control?
Nephropathy
Aggressive control of hyperglycemia and blood pressure are the mainstays of therapy. ACE inhibitors and β blockers are commonly used to control hypertension. LDL cholesterol probably contributes to progression of nephropathy and should be treated if high.
Foot Disease
This is largely avoidable with use of appropriate footwear, education and frequent examination of the foot (put a small mirror on the floor if patient cannot bend to see bottoms of feet). When complications of trauma or infection become severe, legs are often amputated.
