Medicine 5th year, all lectures/diabetes mellitus (Dr. Taha Mahwy)


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The lecture started on Oct. 24th, 2010 and ended on Oct. 31st, 2010 by Dr. Taha Mahwy.

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Medicine 5th year, all lectures/diabetes mellitus (Dr. Taha Mahwy)

  1. 1. Diabetes mellitus Is a clinical syndrome characterized by hyperglycemia duo to absolute or relative insulin deficiency? So carbohydrate, protein & fat metabolism are affected. Acute decompensated complication lead to death while chronic metabolic derangement leads to permanent & irreversible functional & structural change in the cells of the body lead to complication of diabetes. Epidemiology: Blood glucose distribution is unimodal with no clear division between normal & abnormal. Current diagnostic criteria for diabetes have been selected on the bases of identifying those who have a degree of hyperglycemia which has been shown to be associated with a significantly increased risk of disability & death from vascular disease, irrespective of the basic cause of the hyperglycemia. Diabetes is by far the most common of the endocrine disorder. Difference in both genetic & environmental factor for diabetes make prevalence of both type of diabetes varies in different countries, e.g. In Britain is 2-3 % majority have primary diabetes & ratio of type 2: type 1 is 7:3. In other countries: 80-90% type2, 10-20% type1. In USA the prevalence of diabetes is 2-4%. Classification of diabetes mellitus: * Primary: 1. Type 1 DM-previously called insulin dependent diabetes (IDDM). 2. Type 2 DM-previously called non insulin dependent diabetes (NIDDM). * Other specific type of diabetes: 1. Pancreatic: • Pancreatitis • Neoplastic • Haemochromatosis • Pancreatectomy • Cystic fibrosis 2. Excessive endocrine hormone antagonist to insulin: • GH ( acromegaly) • Glucocorticoid ( Cushing syndrome) • Thyroid hormone( thyrotoxicosis) • Glucagons ( glucagonoma) • Catecholamines (Phaeochromocytoma) • human placental lactogen ( pregnancy) 3. Medication: steroid, thiazide, phenytoin, vacor (rodenticide) 4. Liver disease. 5. Associated with genetic syndromes: e.g. • DIDMOAD syndrome • Muscular dystrophy • Friedreich`s ataxia • Down's syndrome 1
  2. 2. • Klinefelter’s syndrome • Turner's syndrome. * Gestational diabetes. Etiology: Environmental factor & genetic both interact to identify those with the genetic predisposition. Type 1 Diabetes: It is a polygenic inheritance, about 95% of type1 DM is HLA DR3 or 4, but since 50% of population is also HLA DR3 or 4, search for type1 DM specific HLA gene continued, & it is mainly related to amino acid at position 57 of HLA DQ β chain. E.g. aspartic acid positive homozygosity has HLA linked resistance to the development of type 1 DM while aspartic acid 57 negative homozygosity (alanine, valine, and serine) substituted for aspartate has maximum susceptibility. Other factors may play role e.g. environmental factor or auto immune factor for pancreatic cell destruction. The concordance rate between monozygotic twins is < 40%. Environmental factors: 1. Viruses: infecting the β cells, mumps, hepatitis, infectious mononucleosis, congenital rubella, Coxsackie's virus B4, cytomegalovirus, mengo virus. 2. Diet: in certain circumstances diet may influence the development of human type1 DM, e.g. anti-gliadin Abs reported in 54% of children (non of whom had celiac disease) at diagnosis of type1DM under 2 years of age. Other diet as wheat & milk protein, bovine serum albumin(BSA) a major constituent of cow's milk and coffee have been shown to have the strongest diabetogenic effect & are evidently are capable of triggering the string of events which results ultimately in destruction of pancreatic islet insulin secreting cells. 3. Stress: stress may progress the development of type 1 diabetes by stimulating the secretion of counter-regulating hormones and possibly by modulating immune activity. 4. Immunological factors: hyperglycemia occurs with clinical symptoms of DM only when 90% of insulin secreting cells is already destroyed. There are many evidences that type1 DM is a slow autoimmune disease as: -HLA- linked genetic predisposition. -associate with other autoimmune disease. -presence of circulating islet cells & insulin auto antibody in new cases. -recurrence of insulitis & selective destruction of insulin secreting cells in pancreatic grafts. Pancreatic pathology: A: Insulitis: infiltration of islets with mononuclear cells B: patchiness of the lesion. C: β cell specifity of the destructive process within infiltrative islets where the glucagons & other hormones (somatostatin) remain intact & finally regression of infiltration. Type 2 Diabetes: A: Genetic factors: Type 2 diabetes is not HLA linked & no evidence that autoimmunity or virus has any effect but study of monozygotic twins that concordance rate 100% for type2 DM reveals that genetic factor is more important, type 2 DM is commonly 2
  3. 3. associated with several other disorders such as obesity, hypertension &hyperlipidemia, this cluster is a specific entity (syndrome X-or the metabolic syndrome) with insulin resistance being the primary defect. A mutation of the glucokinase gene is associated with some cases of the uncommon syndrome of maturity onset diabetes in the young (MODY), constitute less than 5% of all cases of type 2 diabetes. B: Environmental factors: life style, obesity & underactivity are associated with the development of type2 DM. Obesity probably acts as diabetogenic factor (through increasing resistance to the action of insulin) in those genetically predisposed to develop type2 DM. 85% of type2 DM are obese, 15% of type2 DM are non obese, but not all obese person develop diabetes, only few obese people develop diabetes. C: age: Type2 DM is principally disease of middle age & elderly. D: Pregnancy: In young ages diabetes is more in male than female, in middle age female are more. During pregnancy HPL increase leading to anti insulin effect, so pancreas secretes more insulin, in women genetically predisposed to diabetes may not be able to meet these demands & both types of diabetes may occur. Gestational diabetes is hyperglycemia occurring for the 1st time during pregnancy. This may or may not disappear after delivery. Repeated pregnancy increase the risk of permanent diabetes particularly in obese women. 80% of patients with gestational diabetes develop permanent diabetes & require treatment. E: pancreatic pathology: There is only moderate reduction of total mass of islet tissue. There are some typical pathological changes in pancreas in type2 patients, the most consistent of these changes is probably deposition of amyloid which accompany atrophy of normal tissue, particularly islet epithelial cell. Heavy deposition of islets with amyloid is rare without diabetes, but small quantities are very common in elderly non diabetic patients. Etiology of type2 DM is not only by simple deficiency of insulin, but other factors are: 1. Increase hepatic production of glucose. 2. Insulin resistance which usually accompanies obesity this includes: • Abnormal insulin molecule • An excessive amount of circulating antagonists. • Target tissue defect(common cause) Pathophysiology: Whatever the etiology, in all cases the hyperglycemia of diabetes develops because of an absolute (type1) or a relative (type2) deficiency of insulin leads to -decrease metabolism -increase catabolism Insulin has profound effect on carbohydrate, protein, fat and electrolyte metabolism, it has anabolic effect and anticatabolic effect, so balance of these effects in the fasting, post absorptive state, after food, and during exercise is controlled by: 1. Variation in relative concentration of insulin, the only anabolic hormone and several catabolic hormones, namely: glucagons, growth hormone, cortisol, catecholamine and thyroid hormone. 3
  4. 4. 2. Insulin exerts its anticatabolic effect in lower range for that of anabolic effect. During 1st 1.5 hour of meal increase insulin, decrease growth hormone and glucagons. At rest 90% of energy requirement of muscle come from fatty acids & ketone bodies, initially in exercise glycogen from liver oxidized, increased peripheral uptake of glucose and nonesterified fatty acid by increased insulin receptor affinity, then glycogen store is depleted rapidly, so glucose fall, insulin fall, and anaerobic glycolysis start, Catecholamine and cortisol levels increase stimulating lipolysis and gluconeogenesis (formation of glucose from amino acids).the increase in hepatic production matches the increased extra hepatic utilization so that glucose level not changes markedly. As anaerobic glycolysis continue blood lactate concentration increase and this is recycled by the liver as new glucose. In the absence of insulin there will be: 1. Decrease peripheral utilization of glucose. 2. Increase hepatic glucogenesis from liver to circulation. So there is: 1. An extracellular glucose excess. 2. Intracellular glucose deficiency. There is also a decrease in amino acid entry to muscle, & an increase in lipolysis. If hyperglycemia develops over many months or many years as in type2, the renal threshold for glucose rise & features of diabetes are slight that is why many cases of type2 DM are not diagnosed. Clinical feature: Distinction between type1 and type2 DM Type1 DM Type2 DM Age of onset <40 years >50 years Duration of symptoms Weeks Months-years Body weight Normal or low Obese Ketonuria Yes No Autoantibody &other autoimmune disease Yes No Diabetic complication at diagnosis No Yes 10-20% Family history of diabetes No Yes Acute complication Ketoacidosis Hyperosmolar nonketotic coma Overlap occurs particularly in age e.g. MODY: maturity onset diabetes in young people. LADA: latent autoimmune diabetes in adult: some people with apparent type 2 DM have evidence of autoimmune activity against pancreatic β cells. And may have slowly evolving variant of type1 DM. 4
  5. 5. The classical symptoms of polyuria, thirst, polydipsia, recurrent blurred vision, error of refraction, parasthesia( usually when the onset is sub acute) fatigue are manifestations of hyperglycemia & osmotic diuresis & are therefore more common to both types of Diabetes however many patients with type2 diabetes have an insidious onset of hyperglycemia and may be relatively asymptomatic initially particularly in obese patient. In type1, weight loss despite normal or increased appetite is a common feature. Nocturnal enuresis duo to polyuria may signal the onset of diabetes in very young children, when the condition is severe and of acute onset, DKA with features of dehydration, hypotension, acidosis, drowsiness, stuperous, coma may be the presenting feature. Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. Occasionally an initial episode of DKA is followed by a symptom interval in type1 diabetic during which no treatment is required usually it lasts weeks to months, but sometimes may reach 1-2 years, and this is called honey moon period in diabetes. In type2 chronic skin infection are common, generalized pruritis, pruritis vulvae, or balanitis is a common presenting symptom, due to fungal(candidia) infection of external genitalia, which flourish on skin and mucous membrane contaminated by glucose. Diabetic retinopathy, depression or loss of tendon reflex on ankle and impaired perception in the legs indicates neuropathy. Proteinuria in addition to glycosuria in nephropathy, signs in atherosclerosis are common. These were features of established DM. Two other conditions present: One is potential diabetes, the other is latent diabetes. In potential diabetes there is normal glucose tolerance test (GTT) but increase risk of diabetes for genetic reason e.g. children of 2 diabetic parent chance: 15-20%. Latent diabetes There is normal GTT but in conditions cause burden on Pancreases as pregnancy, infection, mental and physical stress or during treatment with corticosteroid, thiazide, or when overweight leads to abnormal result. Potential & latent diabetes usually complain of no symptoms & usually shows no abnormality on exam. Investigation Urinanalysis -Glycosuria: Best to do it 1-2hours after main meal which select much milder cases than fasting urine. Disadvantage is individual variation in renal threshold for glucose. It can be done by using clinitest tablet or by using dipstick method. Differential diagnosis of glycosureia: Although glycosuria reflects diabetes over 90% of patients 2 major classis of nondiabetic glycosuria must be considered. A-Non diabetic glycosuria due to glucose. Glucose appeared in urine despite normal blood glucose e.g. Fanconi’s syndrome, dysfunction of the proximal renal tubules, chronic renal failure, pregnancy(common to have glyosuria by ↑GFR during pregnancy&↑glucose load 50% of pregnant has sugar in urine specially after the 1st trimester&in the last weeks lactose may be present). B-Non diabetic glycosuria due to sugars other than glucose, lactosuria during late pregnancy&lactation is most common e.g. C-Alimentary glycosuria (lag storage). 5
  6. 6. Normal or after gastric surgery or hyperthyroidism or hepatic disease, this is benign &not related to diabetes. Ketonuria: By using Acetest tablet or Ketostix&Ketodiastix, utilize a Nitroprusside reaction, measuring only acetone&acetoacetic acid. Conditions leads to ketonuria apart from DKA are starvation, high fat diet, alcoholic ketoacidosis &fever. Blood glucose estimation Glycosylated Hb; HbA1 reaction between glucose &N-terminal amino acid of both β chains of the Hb molecule. Normally 5-8% and give good diabetic control within preceeding2-3 months .a rise of 1% in HbA1C correspond to an approximate average↑ of 2mmol/L in blood glucose .HbA1C may be diminished in anemia&pregnancy and may be difficult to interpretate it in patients with uremia or haemoglobinopathy. It’s not used as a diagnostic method in diabetes mellitus. Diagnosis of DM: When laboratory facilities are very limited, typical diabetic symptoms with glycosuria may have to suffice to make the diagnosis, ideally however, confirmation with blood glucose or plasma glucose level is best, the diagnosis should be definite as life long treatment &follow up are implied Diagnostic criteria I-Symptoms of diabetes + one abnormal blood glucose level. 2-If symptoms are absent, two abnormal blood glucose level Abnormal blood glucose is: --Fasting plasma glucose≥126mg/dl, after an overnight (at least 8hour) fast. --Random plasma glucose concentration ≥200mg/dl 3-In doubtful cases, a diagnostic GTT (Glucose tolerance test) Indications for oral GTT; •Fasting plasma glucose is 110-126mg/dl •Random plasma glucose is 140-199mg/dl Oral GTT The patient should be on unrestricted CHO diet for 3 days ,fast overnight ,outpatient should rest for half hour, stop smoking ,fasting plasma glucose is measured ,75gm glucose in 300ml of water is given then after 2 hour plasma glucose is measured. The test is interpretated as follow 6
  7. 7. Normal Glucose Tolerance Impaired Glucose Tolerance(IGT) Diabetes Mellitus Fasting plasma glucose (mg/dl) <110 110-125 ≥126 Two hours after glucose load (mg/dl) <140 ≥140but <200 ≥200 IGT (Impaired glucose tolerance) &IFG (Impaired fasting glucose) both terms refer to a stage intermediate between normal and diabetes. IGF refers to a level of plasma glucose between 110-126mg/dl. Many patients with IGT (20-30%) later develop permanent diabetes, which is virtually always type2 DM, many of these are obese & simple dietary advice should be offered. Note: Plasma or serum glucose levels are 10-15% higher than whole blood glucose because structural components of blood cells are absent so that more glucose present per unit volume. Management of DM Three methods of treatment are available for diabetic patients: 1/ diet alone, 2/ diet & an oral hypoglycemia drug, 3/ diet & insulin. Approximately 50% of new case of diabetes can be controlled adequately by diet alone, 20-30% will need an oral hypoglycemic drug& 20-30% will require insulin. Regardless of etiology the type of treatment required is determined by the circulating plasma immunoreactive insulin concentration. At a clinical level the age & weight of the patient at diagnose are closely correlated with the plasma insulin concentration& indicate with a high degree of probability the type of treatment likely to be required. However the regimen eventually adopted in each individual case is chosen by therapeutic trial. Dietary management The daily energy requirement should be decided according to age, sex, actual weight, activity& occupation. e.g. an obese middle aged or elderly person 1000- 1600 Kcal daily. An elderly person not over weight 1400- 1800 Kcal/ day A young active person 1800- 3000 Kcal/ day The body wt. should be maintained at or slightly below the ideal for the patient height. The proportion of energy derived from CHO, protein & fat should be as follow. CHO 50- 60% Protein 10-15% 7
  8. 8. Fat 25- 35% All the CHO prescribed should be taken in the form of starches and other complex sugars. Simple sugars such as glucose & sucrose should generally be avoided because they may cause a sudden rise in the blood glucose concentration. Fiber- rich foods (e.g barley, oats, legumes, beans & lentils) has been associated with improved blood glucose control & lower blood lipids in both normal, diabetic & hyperlipidemic persons. Excessive salt intake is to be avoided; it should be particularly restricted in people with hypertension & those with nephropathy. In addition to reducing calorie intake, overweight patients should be strongly encouraged to take regular exercise, in the form of walking, swimming or cycling, for approximately 30 minutes daily, as this improves insulin sensitivity and the lipid profile and lowers blood pressure. Drug treatment for type2 DM: Oral hypoglycaemia drugs (OHD) Are considered only after a regimen of dietary treatment combined with exercise has failed to achieve the therapy targets set. There are (2) major groups of OHD. Sulphonylureas (SUs) and biguanides (BGs) SU act by stimulating insulin release from the β cells (insulin secretagogue).They act through a sulphonylurea receptor which is linked to a k+ channel on the β-cell surface .k+transport triggers insulin secretion. BG exerts their action by ↓ gluconeogenesis & by ↑ the peripheral utilization of glucose. Selection of a specific SU preparation will depend on factors such as availability, cost, and the physician's experience. SUs can cause hypoglycaemia and their use should therefore be closely monitored in the elderly & in those with nephropathy. Tolbutamide is a short- acting SU and may be selected in Patients with renal impairment. The initial daily dose is 0.5 gm, which can be ↑ if necessary to 1.5 gm in divided doses. Chlorpropamide has a half- life of about 36h the usual maintenance dose is 100- 350 mg/ day. toxic effects include cholestatic Jaundice, skin rash & blood dyscrasia. Feature of disulfiram- like reaction occur in some patients after taking alcohol. Occasionally chlorpropamide can induce (SIADH). ▪ Of the second generation sulphonylureas. gliclazide and glipizide cause few side- effects but glibenclamide is proving to induce sever hypoglycemia and should be avoided in elderly. newer long acting preparation such as glimepiride and a modified- release form of gliclazide can be administered once daily with no apparent ↑ risk of hypoglycaemia. Glibenclamide may be given in an initial dose of 1.25- 2.5 mg which can be ↑ up to a maximum daily dose of 15 mg. Metformin is the only BG preparation now marketed in most Easters Mediterranean region countries. Metformin is primarily used in the obese not responding to dietary therapy. The starting dose is 500- 850 mg with or after food, once daily, which can be ↑ to 500 mg tds or 850 mg b.d because of the risk of lactic acidosis its contraindicated in: - Patients with impaired renal function. - Elderly people above the age of 70 years. 8
  9. 9. - Patients with heart failure, hepatic impairment, or predisposition to lactic acidosis. For the same reason, treatment with metformin should be discontinued during surgery, sever infection & intercurrent illnesses. SU may be combined with metformin, when therapy targets are not achieved with either drug pregnancy in certain cases metformin or glibenclamide(the only sulphonylurea that dose not cross the placenta)is used. Other oral hypoglycaemia drugs: Alpha- glucosidase inhibitors: They delay CHO absorption in the gut by selectively inhibiting disaccharidases. Acarbose (Glucobay) is currently available and is taken in a dose of 50- 100 mg with each meal. It principally lowers post- prandial blood glucose, modestly improves overall glycaemic control & reduces HbA1C. Acarbose can be combined with a sulphonylurea. The main side effects are flatulence, abdominal bloating and diarrhea. Thiazolidinediones They are a new class of compound for treatment of type 2 D.M. they work by enhancing the action of endogenous insulin. Insulin sensitivity is improved only in patients with insulin resistance. Plasma insulin concentrations are not increased & hypoglycemia is not a problem. The beneficial non- hypoglycemic effects of this compound include ↓ in plasma insulin & triglyceride levels, ↑ in HDL cholesterol level. ↓ Lipid oxidation, favorable redistribute of body fat. ↓ In vascular resistance. & improvement in endothelial function but deleterious effect includes elevation of LDL cholesterol level, oedema& weight gain. The e.g. of there drugs are Rosiglitazone & Pioglitazone, they may cause liver failure. The 1st drug to be commercially available is troglitazone. Meglitinide and amino acid derivatives; These drugs are oral prandial glucose regulators. Repaglinide directly stimulates endogenous insulin secretion and is taken immediately before food. It's less likely to cause hypoglycemia than sulphonylurea. Nateglinide has a similar mode of action, restores first- phase insulin secretion, and is prescribed with metformin. New Products: Incretin Mimetics The incretin mimetics are medications that mimic the action of incretins, peptide hormones that originate in the gastrointestinal tract.Glucagon –like peptide(GLP-1)is an incretin hormone are released during nutrient absorption, augmenting insulin secretion. They also reduce postprandial glucagon secretion and delay gastric emptying time. As a result, patients using these medications can have improved postprandial glucose excursions and early satiety.Incretin hormones have a very short life-span in circulation as they are rapidly destroyed by DPP-IV (Dipeptyl Peptidase-IV).By opposing the action of DPP-IV the drug Sitagliptin helps to prolong the incretin effect. this helps reduce blood glucose level.Sitagliptin is taken orally once daily the tablets are 100mg.side effects are uncommon ,nausea flatulence when combined with glitazone swelling of the feet may be seen, hypoglycemia may occurs, its contraindicated in type1 DM,previously had diabetes ketoacidosis and renal problem. Synthetic GLP-1 receptor antagonists with longer therapeutic action include exenatide(synthetic exendine 4)and liraglutide.incretin-based therapies are most useful in obese patients and can be used in combination with other oral anti-diabetic agents. 9
  10. 10. Insulin: It's indicated in type2 DM in the following situations 1/ when diet & OHD fail to control hyperglycemia and achieve therapy targets. (Fasting plasma glucose level 80- 120 mg/ dl, post prandial 90- 145 mg/dl is optimal, fasting plasma glucose level less than 160 mg/ dl, post prandial less than 180 mg/dl is acceptable while fasting plasma glucose level more than 160 mg/dl and post prandial more than 180 mg/dl is poor). 2/Diabets during pregnancy when diet alone is inadequate. 3/ when OHD are contraindicated. 4/ during stressful conditions such as infection & surgery. Management of type1 DM: The principles, guidelines and recommendation made for type2 DM generally apply to type1DM. Insulin therapy: Insulin therapy aims at: 1/ achieving good metabolic control by mimicking physiological insulin secretion as much as possible. 2/minimizing the risk of hypoglycemia. Matching insulin requirement with CHO intake & physical activity & combining it with frequent self monitering are prerequisites for a successful therapeutic strategy in type1 DM. Insulin are either bovine or porcine, human insulin produced by recombinant DNA technology recently rDNA & protein engineery technique, that alters the Amino Acid sequence of insulin have been used to produce (nonomeric) analogues of insulin which are more rapidly absorbed from the site of injection. (e.g. lispro or aspart) Insulin preparation of any species may be used. Two major types of insulin preparations are usually used: short- and intermediate acting. Except in occasional circumstances, long acting insulin are generally not needed. The strength of insulin and the calibration of syringes should be uniform throughout the country, for example 40- 100, in order to avoid confusion. Insulin is usually given by the s.c route, i.v or i.m routes may be used in emergencies such as in cases of diabetic ketoacidosis. The use of other routes such as intraperitoneal or nasal is still in the experimented stage. - Implantable insulin pumps are still in the experimental stage. - Injection should be given in to the deep s.c tissue at a 45° angle or at a 90° angle when the s.c layer is greater than the needle length. - Rotation of injection sites is recommended to reduce insulin injection site damage. - Absorption from the abdomen is faster than from thighs or upper arms and may be preferred for short- acting preparation. Insulin regimens: 10
  11. 11. - The majority of pts will require more than one daily injection if good glycaemic control is to be achieved. However a once- daily injection of an intermediate acting preparation may be effectively used in some patients. - Twice- daily mixtures of short- and intermediate acting insulin is a commonly used regimen. - In some cases, a mixture of short- and intermediate acting insulin may be given in the morning. Further dose of short- acting insulin are given before lunch and the evening meal and an evening dose of intermediate- acting insulin is given at bed time. Other regimens basal on the same principles may be used. - A regimen of multiple injection of short- acting insulin before the main meals, with an appropriate dose of intermediate- acting insulin given at bed time, may be used, particularly when strict glycaemic control is mandatory. The dose of the insulin preparations is adjusted according to frequent monitoring of blood glucose levels. Blood glucose monitory should be intensified during intercurrent illness & other stressful conditions & the insulin dose may have to be ↑. Follow- up: Emphasis should be placed on the importance of regular follow- up. During follow up visits, education should be reinforced, growth monitored, blood glucose monitoring results reviewed, & measurement of HbAlc, urine glucose & ketones. Following puberty, & more than 5 years after diagnosis, annual eye examination with assessment of the retina& testing for micro albuminuria are recommended. Factors associated with ↑ mortality & morbidity in diabetic patients. • Duration of diabetes. • Early age at onset of disease. • High glycated Hb. • Raised B.P. • Proteinuria. • Obesity. • Hyperlipidemia. Acute complications of diabetes: Includes hypoglycaemia, diabetic ketoacidosis. Non- ketotic hyperosmolar diabetic coma, Lactic acidosis and acute circulating failure. Hypoglycaemia: Defined as a blood glucose concentration of less than 45 mg/dl, common in those taking insulin in comparism to suphonylurea drugs. Sever hypoglycaemia defined as hypoglycaemia requiring the assistance of another person for recovery. Can result in serious morbidity, and has a recognized mortality of 2-4% in insulin- treated patient. When hypoglycemia develops in non-diabetic people, it is called `spontaneous hypoglycemia. Symptoms of hypoglycaemia: 11
  12. 12. Including those related to acute activation of the autonomic N.S and those secondary to glucose deprivation of the brain (neuroglycopenia). Symptoms of autonomic activation includes sweating, trembling, pounding heart, hunger and anxiety. Neuroglycopenic symptoms including confusion, drowsiness, speech difficulty, inability to concentrate and incoordination. Non- specific features are nausea, tiredness and headache. Cause and prevention The most common cause is unpunctual or in adequate meals, unexpected or unusual exercise, and ingestion of alcohol other causes includes defective glucose counter – regulator /unawareness of hypoglycemia, gastroparesies due to autonomic neuropathy Presence of other endocrine disorders e.g. Addison's disease. Nocturnal hypoglycemia occur because the basic cause is the physiological diurnal variation in the amount of insulin required to achieve homeostasis which is probably related to the diurnal rhythm in the secretion of counter-regulatory hormones such as glucocorticoid and Growth hormone which are insulin antagonists . Diagnosis is by measuring blood glucose between 2:00 and 3:00 hours and the treatment by: -Split evening dose of insulin -take unmodified insulin not before 23:00 hours. Management of hypoglycemia If pt. able to swallow, glucose should be given orally. In diabetics with depot insulin or sulphonylurea particularly chlorpropamide there is possibility of relapse. In emergency Tx I.V glucose given as 50 ml. of 50% dextrose ,localized thrombophilibitis is the hazard .On regaining conscious the pt. should be given oral CHO and continuous I.V infusion of dextrose (5%or 10%)may be necessary to prevent recurrence of hypoglycemia .I.M glucagon (1mg)may be of value may be ineffective if hepatic glycogen store are depleted as in prolonged starvation , if pt. fail to regain conscious cerebral edema should be considered other causes include alcoholic intoxication, a postictal state or cerebral hemorrhage and C.T scan of brain may be necessary . Cerebral edema has high mortality and morbidity and needs treatment with mannitol and/ or dexamethasone. Diabetic ketoacidosis Nowadays this complication account for 2% of deaths among diabetes and prior to discovery of insulin was more than 50%. Mechanism underlying the development of ketoaidosis: In the presence of marked insulin deficiency suppression of lipolysis is lost and plasma concentration non-esterified fatty acids may remain constantly elevated. Fatty acids are taken up by the liver and degraded through 8 steps within the mitochondria of the liver cells. Each stage yields one molecule of acetyl coA. normally most of these molecules enter the citric acid cycle by condensing with oxaloacetic acid but in the absence of insulin more is formed than can enter the citric acid cycle, and acetyl coA is converted to acetoacetic acid, most of this is then reduced to β hydroxyl butyric acid, while some is decarboxylated to acetone. These ketone bodies when formed in small amounts are oxidized and utilized as metabolic fuel. When the rate of ketone production by the liver exceeds that of removal by the peripheral tissue, then hyperketonemia results. 12
  13. 13. Ketone bodies increase osmolality of plasma so leads to withdrawal of water from the cells. They release Hydrogen ion from body fluids and lead to fall in pH and HCO3- usage, so HCO3-/H2CO3 fall and increase hydrogen ion leads to stimulation of pulmonary ventilation and air hunger. Clinically the severity of ketoacidosis can be assessed rapidly by measuring the plasma HCO3- , if less than 12mmole/L indicates severe acidosis, the average loss of fluid and electrolyte in moderately severe DKA in adults is as follows: --Water 6 liters; about half from intracellular compartment, the reminder is loss of extra cellular fluid. --Na loss 500 mmole --Chloride 400mmole --K 350 mmole Every patient in DKA is potassium depleted but the plasma content of K gives very little indication of the total body deficit. Clinical feature: The state of consciousness is very variable in DKA; a patient with dangerous ketoacidosis, requiring urgent treatment may walk into the consulting room. For this reason the term DKA is to be preferred to (diabetic coma). Features of DKA can be compared with that of hypoglycemia as follows: Hypoglycemia Coma with ketosis History No food, too much insulin, unaccustomed exercise Too little or no insulin, an infection or digestive disturbance Onset In good previous health relative to last insulin injection Ill-health for several days Symptoms That of hypoglycemia, occasionally vomiting Of glycosuria & dehydration, abdominal pain & vomiting Signs Moist skin & tongue, full pulse, normal or raised systolic blood pressure, shallow or normal breathing, brisk reflexes Dry skin & tongue, weak pulse, low blood Pressure, air hunger diminished reflexes. Urine No ketonuria No glycosuria Ketonuria Glycosuria Blood Hypoglycemia Normal plasma bicarbonate Hyperglycemia Reduced plasma bicarbonate Management: DKA should be treated in hospital, IV fluid replacement is required since even the patient is able to swallow fluid given by mouth may be poorly absorbed, the components of treatment are: - Insulin: 13
  14. 14. Use only Unmodified clear insulin, start IV insulin infusion 5 unit/hour, if this is not practical so a loading dose of 10-20 units can be given i.m, & immediately followed by 4- 6 units hourly, the blood glucose concentration should fall by 55-110 mg/dl/hour. If after 2 hour from treatment no fall, then the dose of insulin should be doubled, until a satisfactory response is obtained. When the blood glucose concentration has fallen to 180-250mg/dl the dose of insulin should be reduced to 1-4 units hourly. -fluid replacement: Average fluid deficit is 6 liter: 3liters extra cellular replace by saline 3 intracellular replaced by glucose Early rapid rehydration by isotonic saline (0.9% Nacl) is essential; otherwise the administered insulin will not reach the poorly perfused tissue. If the plasma Na greater than 155 mmole/liter so 0.45% saline may be given initially instead of 0.9%, NaHCO3 indicated in pH <7.1 in the presence of: 1. Hypotention 2. Arrhythmia 3. Coma 300-500 cc of 1.26% NaHCO3 may be given over 30 minutes into a large vein, otherwise correction of the total bicarbonate deficit should not be attempted because rapid correction 1. Aggravate tissue hypoxia 2. Reduce consciousness by paradoxical acidosis of CSF 3. HCO3 & insulin increase risk of hypokalemia The intracellular water deficit must be replaced by using 5 or 10% dextrose & not by more saline; it is best given when the blood glucose concentration approaches normal. -potassium: KCL should be started cautiously initially but according to frequent estimation of K-level; it can be given as the following 1. If plasma K more than 5.5 mmol/L give no K 2. If 3.5-5.5 mmole/l give 20mmole KCL/L of infused fluid. 3. If<3.5mmol/L give 40 mmole KCL/Litter of infused fluid. -Antibiotics: Infection must be carefully sought & vigorously treated, leukocytosis is invariably seen in DKA this represents a stress response & doesn’t necessarily indicate infection, and also pyrexia may not be present initially because of vasodilatation secondary to acidosis. Additional procedures which may be required: -catheterization if after 3h no urine passed -nasogastric tube to keep stomach empty (in unconscious or semiconscious patient) -Central venous line if C.V.S. compromised. -plasma expander if BP doesn't rise with IV saline. Precipitating cause of DKA: 1. Infection: overwhelming infection precipitate DKA in type2DM. 2. Erratic insulin supply. 3. In type2 DM who have failure of treatment by oral hypoglycemic agents & need insulin, so when they refuse to take it, leads to DKA 14
  15. 15. 4. Acute MI 5. C.V.A. 6. Pancreatitis 7. Massive trauma or other serious illness. Mortality: 2-5% mostly in: 1. Elderly 2. Serious complicating illness 3. Those who present in coma Complication of DKA: 1. Fluid overload, cerebral oedema 2. hypoglycemia 3. Hypo& hyperkalemia 4. Thromboembolism 5. ARDS 6. Acute gastric dilatation (rare) 7. Mucormycosis. Poor prognostic sign in DKA at Admission include: Hypotension, azotemia, deep coma Cause of death: Pneumonia MI In children :cerebral oedema . Prevention: 1. Education. 2. Storage of insulin 3. Admission of patient with early signs of ketoacidosis. Non-ketotic hyperosmolar diabetic coma: This condition is characterized by severe hyperglycemia>900mg/dl without severe hyperketonemia or acidosis. Severe dehydration and prerenal uremia are common. This usually affects elderly patients, many with previously undiagnosed diabetes. Mortality is over 40% its treatment is differing from that of ketoacidosis in two main aspects: 1. These patients are sensitive to insulin & approximately half the dose of insulin recommended for the treatment of ketoacidosis is needed. 2. The plasma osmolality should be measured as: Plasma osmolality= 2[Na+] +2([K+] + [glucose] + [urea]), the normal value is 280- 300mmole/kg, and the conscious level is depressed when it is high (>340mmole/kg) The patient should be given 0.45% saline until the osmolality approaches normal, when 0.9% should be substituted through C.V.P. line. Thromboembolic complication is common and prophylactic S.C. heparin is recommended. Lactic acidosis: The patient is likely to be a diabetic taking biguanide who is very ill & over breathing, but not so profoundly dehydrated as in coma of ketoacidosis, plasma HCO3- is markedly reduced (pH, 7.2) Diagnosis by high (usually 5.0mmole/L) concentration of lactic acid in the blood. 15
  16. 16. Treatment with IV bicarbonate to raise pH above 7.2 also give insulin & glucagone. Mortality rate is 50%. Long term complication of diabetes: The excess mortality is mainly due to large blood vessel disease. & accounts for about 70% of all death. The pathological change associated with atherosclerosis in diabetic patient are similar to those seen in the non diabetic population but they occur earlier in life and are more extensive & sever. Diabetic microangiopathy is disease of small blood vessel it contributes to retinopathy &nephropathy. In pathology of the diabetic microangiopathy there is thickening of the capillary basement membrane with associated ↑ vascular permeability throughout the body. The pathogenesis in diabetic complications is through that to be due to↑ metabolism of glucose to sorbitol via the polyol pathway. Macro vascular disease Arterio sclerosis is a common problem in diabetic because of risk for vascular disease so the risk should be ↓ by stop smoking & H.T should be treated , elevated plasma lipid should be treated it improve with control of hyperglycemia . Silent myocardial infarction because of associated neuropathy & tendency of vascular disease to be more diffuse making vascular reconstructive surgery more difficult, nevertheless the indication & success is not significantly different from others. Diabetic patent with existing cardiovascular disease should receive lipid lowering statin if the plasma total cholesterol concentration is >5.0mmol/L. The frequency & severity of microvasculature complicate of type1DM can be minimized by strike glycaemic control (mean HbA1c around 7%) using intensive insulin therapy. Causes of death in treated diabetic patients: - C.V.D. 70% - Renal failure 10% - Cancer 10% - Infections 6% - DKA 1% - Other 3% 16
  17. 17. Diabetic neuropathy: Classification - Somatic * Polyneuropathy : Symmetrical, mainly sensory &distal Asymmetrical, mainly motor &proximal (Including amyotrophy) * Mononeuropathy (including mononeuritis multiplex) - Visceral (autonomic). * Cardiovascular * Gastrointestinal *Genitourinary * Sudomotor * Vasomotor * Pupillary Symmetrical sensory polyneuropathy. This is frequent asymptomatic, the most commune sign are loss of tendon reflex in the lower limbs ,↓ perception of vibration sense distally & glove and stocking impairment of all other modalities of sensation. symptoms include paraesthesia in the feet and sometime in the hand, pain in the lower limbs(dull aching lancinating worse at night &mainly felt on the anterior aspect of the leg),burning sensation on the sole of the feet &abnormal gait(commonly wide base). -There may be perforating painless ulcer on the feet and painless distal arthropathy characterized by disorganization of the joint (Charcot joint), on investigation both motor and sensory conduction velocity is reduced and C.S.F protein may be raised. For pain and parasthesia treatment is by intensive insulin therapy, tricyclic antidepressant (amitryptiline or imipramine), other drugs are anticonvulsants (gabapentin,pregabalin,carbamazepine and phenytoin) Asymmetrical motor diabetic neuropathy Sometime called diabetic amyotrophy. Present as sever & progressives weakness & wasting of the proximal muscle of the lower limb. And is commonly accompanied by sever pain on the anterior aspect of the leg sometime there may also be marked weight loss (neuropathic cachexia) tendon reflex may be absent on the affected side, again C.S.F. protein is commonly raised. Mono neuropathy Wrist drop .foot drop. 3rd . 4th & 6th cranial nerve palsy & reversibility is high. 17
  18. 18. Autonomic neuropathy This is not necessarily associated with peripheral somatic neuropathy. Feature of autonomic neuropathy. C.V.: postural hypotension, resting tachycardia, fixed heart rate G.I.T.: Dysphagia, gastroparesis, abdominal fullness, nausea. Vomiting nocturnal diarrhea, Constipation. G.U.S: Atomic bladder, impotence & retrograde ejaculation, impotence affects 30% of diabetic male & is often multifactorial. Other features: Gustatory sweating. Dependent edema on pupillay exam then is ↓ pupillay size resistant to mydriasis. Loss of awareness of hypoglycemia. Autonomic neuropathy is less related to poor metabolic control than somatic neuropathy. And improved control rarely results in amelioration of symptoms. Treatment is symptomatic, patients with gastro paresis may benefit from use of metoclopramide .cisapride or erythromycin, diabetic diarrhea may benefit from a trial of antibiotic orthostatic hypotension may be treated with salt tablets, support stocking or 9 α fluorohydrocortisone. Diabetic foot: Callus formula is the initial abnormally usually. Foot ulcer is due to microangiopathy, macroangiopathy (ischemia), neuropathy (plantar surface) or all 3. Management: Removals of the callus skin best done by chiropodist, treat infection, avoid weight bearing, and ensure good diabetic control. (Insulin may be required in type2DM) control edema. Undertake angiogram to assess feasibility of vascular re constriction where indicated. Indication of amputation 1/ uncontrolled infection. 2/Ostiomyelitis. 3/ extensive tissue destruction 4/ in tractable pain at rest in the limb. 18
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