COMPLICATIONS of DIABETES DM is a chronic disease

COMPLICATIONS of DIABETES DM is a chronic disease that can cause complications leading to significant morbidity and premature death Why diet? 2

Diabetes accounts for 60% of all nontraumatic amputations in the United States over 30% of patients hospitalized with acute myocardial infarction have diabetes, and 35% have impaired glucose tolerance 3

Complications of Diabetes Acute complications • • Diabetic ketoacidosis (DKA) Hyperglycemic, Hyperosmolar Coma (HHS) Chronic complications Microvascular complications: • Neuropathy, Nephropathy, Retinopathy Macrovascular complications: • Coronary artery disease, peripheral vascular disease, stroke 4

Acute Complications DKA was formerly considered a hallmark of type 1 DM, but it may also rarely occur in type 2 DM HHS is primarily seen in individuals with type 2 DM Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and acid–base abnormalities 5

Diabetic Ketoacidosis • MEDICAL EMERGENCY!!! • Due to lack of insulin • Most often seen in Type 1 DM but also can be present in Type 2 DM 6

Ketoacidosis. Ketons are produced in the liver from free fatty acids (FFAs) and are metabolized by the extrahepatic tissues. Increased production of ketoacids, the main mechanism for ketoacid accumulation, requires a high concentration of FFAs and their conversion to ketoacids in the liver. Insulin deficiency is responsible for increased mobilization of FFAs from the adipose tissue, Diversion of acetyl-coenzyme A to fatty acid resynthesis requires the enzyme acetyl-coenzyme A carboxylase. Inhibition of this enzyme by insulin deficiency, or an excess of stress-induced hormones further contributes to increased ketoacid synthesis 7

Ketoacidosis • Inadequate insulin leads to energy stores from fat and muscle to be broken down into fatty acids and amino acids • These precursors are transported to the liver for conversion to glucose and ketones 8

In DKA the osmotic force exerted by unreabsorbed glucose and ketones leads to retention of water in the tubule, thereby preventing its reabsorption and leading to fluid depletion. Sodium reabsorption is also retarded, and the net result is marked excretion of sodium and water, which can lead in worst cases to hypotension, brain damage, and death if left untreated 9

In prolonged fasting by nondiabetic persons, ketone body levels seldom rise higher than 6 to 8 mmol/L, but they rise much higher in diabetic ketoacidosis, imposing an acid load too great for the body’s buffering system to absorb and causing a dangerous fall in p. H. This condition is known as ketoacidemia 10

Why is the ketosis of simple fasting mild and clinically benign, whereas the ketoacidosis of diabetes commonly escalates into life-threatening ketoacidemia 11

Two features distinguish severe ketoacidosis from the benign ketoacidosis of fasting: volume depletion and hypermetabolism 12

Volume depletion worsens existing ketoacidosis (and worsens hyperglycemia) in various ways: by reducing blood flow to the kidneys and brain, reducing brain and renal ketone body oxidation, and greatly reducing urinary ketone body excretion 13

Insulin, Na. Cl infusion, and usually additional glucose are required to treat diabetic ketoacidosis Many relatively common medical disorders can lead to hypophosphatemia. One such disorder is diabetic ketoacidosis (DKA). Hypophosphatemia is often observed during the treatment of DKA because the administration of insulin drives glucose and phosphate into cells and causes a rapid fall in extracellular plasma phosphate. 14

Hyperglycemic, Hyperosmolar Coma Patients with type 2 diabetes sometimes develop a condition called hyperglycemic, hyperosmolar coma This is particularly common in the elderly, and it may occur in individuals under severe metabolic stress who were nor previously recognized as having diabetes Hyperglycemia, perhaps worsened by failure to take insulin or hypoglycemic drugs, an infection, or a coincidental medical problem such as a heart attack, leads to urinary losses of water, glucose, and electrolytes (sodium, chloride, and potassium) 15

This osmotic diuresis reduces the circulating blood volume, a physiological stress that releases hormones that worsen insulin resistance and hyperglycemia. In addition, elderly patients may be less able to sense thirst or to obtain fluids. Over the course of several days, they can become extremely hyperglycemic (glucos. > 1000 mgd. L-t), dehydrated, and comatose 16

Ketoacidosis does not develop in these patients, possibly because free fatty acids are not always elevated or because adequate insulin concentrations exist in the portal blood to inhibit ketogenesis (although they are not high enough to inhibit gluconeogenesis). Therapy is aimed at restoring water and electrolyte balance and correcting the hyperglycemia with insulin. Mortality from this syndrome is considerably higher than that of diabetic ketoacidosis 17

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Diagnostic criteria for diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) 19

Chronic Complications Chronic complications occur over years or decades of hyperglycemia and are often difficult or impossible to reverse Examples include microvascular complications (i. e. , small vessel disease) such as retinopathy, neuropathy, and nephropathy or macrovascular complications (i. e. , large vessel disease) such as coronary heart disease, peripheral vascular disease, or stroke 20

Hyperglycemia causes tissue damage through five major mechanisms • Increased flux of glucose and other sugars through the polyol pathway • increased intracellular formation of advanced glycation end-products (AGEs) • increased expression of the receptor for advanced glycation end products • activation of protein kinase C (PKC) isoforms • overactivity of the hexosamine pathway 21

Several lines of evidence indicate that all five mechanisms are activated by a single upstream event : mitochondrial overproduction of reactive oxygen species 22

However, the results of clinical studies in which only one of these pathways is blocked have been disappointing This led to the hypothesis that all five mechanisms are activated by a single upstream event: mitochondrial overproduction of the reactive oxygen species 23

Increased polyol pathway flux The polyol pathway is based on a family of aldo-keto reductase enzymes which can utilize as substrates a wide variety of carbonyl compounds, and reduce these by nicotinic acid adenine dinucleotide phosphate (NADPH) to their respective sugar alcohols (polyols). 24

first thought that glucose is converted to sorbitol by the enzyme aldose reductase, with sorbitol then oxidized to fructose by the enzyme sorbitol dehydrogenase (SDH), with NAD+ as a cofactor. Aldose reductase is found in tissues such as nerve, retina, lens, glomerulus and vascular cells In many of these tissues, glucose uptake is mediated by insulin independent GLUTs; intracellular glucose concentrations therefore rise in parallel with hyperglycemia 25

Several mechanisms have been proposed to explain how hyperglycemia-induced increases in polyol pathway flux could damage the tissues involved. The most cited is an increase in redox stress due to the consumption of NADPH Since NADPH is a cofactor required to regenerate reduced glutathione (GSH), and GSH is an important scavenger of reactive oxygen species (ROS), this could induce or exacerbate intracellular oxidative stress. 26

Increased intracellular AGE formation Advanced glycation end products (AGEs) are formed by the non-enzymatic reaction of glucose and other glycating compounds derived both from glucose and from increased fatty acid oxidation in arterial endothelial cells and most likely heart (e. g. dicarbonyls such as 3 - deoxyglucosone, methylglyoxal and glyoxal) with proteins In diabetes, AGEs are found in increased amounts in extracellular matrix 27

Intracellular production of AGE precursors can damage cells by three general mechanisms • Firstly, intracellular proteins modified by AGEs have altered function • Secondly, extracellular matrix components modified by AGE precursors interact abnormally with other matrix components and with matrix receptors that are expressed on the surface of cells • Finally, plasma proteins modified by AGE precursors bind to AGE receptors on cells such as macrophages, vascular endothelial cells and vascular smooth muscle cells. 28

increased expression of the receptor for advanced glycation end products (RAGE) RAGE binding induces the production of ROS, which in turn activates the pleiotropic transcription factor, (incorrect regulation )nuclear factor kappa B (NFκB), causing multiple pathological changes in gene expression A specific receptor for AGEs (RAGE) has been shown to mediate signal transduction via generation of ROS 29

Increased protein kinase C activation PKC are a family of at least 11 isoforms that are widely distributed in mammalian tissues. The enzyme phosphorylates various target proteins. The activity of the classic isoforms is dependent on both Ca 2+ ions and phosphatidylserine, and is greatly enhanced by diacylglycerol (DAG) This results primarily from enhanced de-novo synthesis of DAG from glucose via triose phosphate, whose availability is increased because increased ROS inhibit activity of the glycolytic enzyme glyceraldehyde 3 phosphate dehydrogenase (GAPDH), raising intracellular levels of the DAG precursor triose phosphate 30

Increased hexosamine pathway flux Hyperglycemia and insulin resistance-induced excess fatty acid oxidation also appear to contribute to the pathogenesis of diabetic complications by increasing the flux of fructose 6 phosphate into the hexosamine pathway 31

In this pathway, fructose 6 -phosphate is diverted from glycolysis to provide substrate for the ratelimiting enzyme of this pathway, glutamine: fructose 6 phosphate amidotransferase (GFAT). GFAT converts fructose 6 phosphate to Glucosamine 6 -phosphate, which is then converted to UDP-NAcetylglucosamine. Specific OGlc. NAc transferases use this for post-translational modification of specific serine and threonine residues on cytoplasmic and nuclear proteins by O-linked N-Acetylglucosamine 32

Inhibition of GFAT blocks hyperglycemia-induced increases in the transcription of both TGF-α and TGF-β 1. While it is not entirely clear how increased flux through the hexosamine pathway mediates hyperglycemia-induced increases in the gene transcription of key genes such as TGF-α, TGF-β 1 and PAI-1, it has been shown that hyperglycemia causes a four-fold increase in OGlc. NAcylation of the transcription factor Sp 1, which mediates hyperglycemia-induced activation of the PAI-1 promoter in vascular smooth-muscle cells and of TGF-β 1 and PAI-1 in arterial endothelial cells. Of particular relevance to diabetic vascular complications is the inhibition of endothelial nitric oxide synthase (e. NOS) activity in arterial endothelial cells by O-Glc. NAcylation at the Akt activation site of e. NOS protein 33

A single process underlies different hyperglycemia -induced pathogenic mechanisms: Mitochondrial superoxide production 34

Superoxide is the initial oxygen free radical formed by the mitochondria, which is then converted to other more reactive species that can damage cells in numerous ways 35

Normally, electron transfer through Complexes I, III and IV extrudes protons outwards into the intermembrane space, generating a proton gradient that drives ATP synthase (Complex V) as protons pass back through the inner membrane into the matrix In contrast, in diabetic cells with high intracellular glucose concentration, there is more glucose-derived pyruvate being oxidized in the TCA cycle, increasing the flux of electron donors (NADH and FADH 2) into the electron transport chain. 36

As a result, the voltage gradient across the mitochondrial membrane increases until a critical threshold is reached. At this point, electron transfer inside complex III is blocked, causing the electrons to back up to coenzyme Q, which donates the electrons one at a time to molecular oxygen, thereby generating superoxide 37

It has been also demonstrated that dynamic changes in mitochondrial morphology are associated with high glucose-induced overproduction of ROS 38

Neither hyperglycemia nor increased fatty acid oxidation in vascular endothelium increases ROS nor activates any of the pathways when either the voltage gradient across the mitochondrial membrane is collapsed by uncoupling protein 1 (UCP-1) or when the superoxide produced is degraded by Mn. SOD In the diabetic heart, overexpression of Mn. SOD or catalase protects cardiac mitochondria from oxidative damage Mn. SOD also prevents the morphological changes in diabetic hearts and completely normalizes contractility in diabetic cardiomyocytes 39

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Treatment Lowering A 1 C below or around 7. 0% has been shown to reduce: Micro & Macrovascular complications DM is manageable. Its complications are not inevitable with optimal glycemic control and cardiovascular risk factor management, and they can be treated if they occur 41

outlines • CHO counting + Antioxidant therapy specially in low SES • Track of Hb. A 1 c • In uncontrolled condition • The best approach (strengthen endogenous ) • In interventional study ( best outcome to measure ) 42