Clinical forms and treatment of diabetes mellitus

Clinical forms and treatment of diabetes mellitus Symptomes of hyperglycaemia Because of the blood sugar level exceeds the renal treshold of glucose: • Frequent urination = polyuria • Intense thirst = polydipsia • Increased urge to eat = polyphagia • Wasting of body flesh Because of other causes: Fatigue, candida infections, vulvovaginitis, balanitis, blurred vision (osmotic swelling of lenses) Complications Acute: diabetic ketoacidosis and noketotic hyperosmolar coma • Chronic: microvascular, macrovasular • • Insulin deficiency Absolute (T1DM) 0,2% Relative (T2DM) 2% - 4% prevalence hyperglycaemia symptomes + complications Classification and diagnostic criteria of different forms of carbohydrate intolerance • Upper limit of normal fasting blood sugar level: 6,1 mmol/l • Upper limit of the two-hours blood sugar level during an OGTT with 75 g of glucose: 7,77 mmol/l Impaired glucose homeostatsis: • Impaired fasting glucose (IFG): fasting blood sugar level is between 6,2 and 6,99 mmol/l • Impaired glucose tolerance (IGT): two hours blood sugar level during an OGTT is between 7,8 and 11,1 mmol/l. Diabetes mellitus: fasting blood glucose is >7 mmol/l, random blood glucose >= 11,1 mmol/l, two hours blood glucose level during an OGTT is >= 11,1 mmol/l The clinical forms of diabetes mellitus Primary diabetes mellitus manifested in adulthood • Polygenic type 2 diabetes mellitus • MODY (maturity onset diabetes in the young) mutation of the genes of glucokinase and hepatic nuclear factor alpha 1-4 • MIDD (maternally inherited diabetes and deafness) mitochondrial gene mutation • Mixed type 1 and type 2 diabetes mellitus • LADA • Type 1 diabetes mellitus • Gestational diabetes mellitus (GDM) Classification based on the clinical picture is not always possible. The patient can visit the doctor because of • Sudden deterioration of carbohydrate netabolism with serious hyperglycaemia, ketoacidosis, exsiccosis (dry, warm skin; deep and frequent breathing; aromatous-acetonic smell; exsiccosis; abdominal pain; alteration of the mental status; disorientation; coma). • Longer duration of typical symptomes of hyperglycaemia with ketonuria. (Type 1 diabetes mellitus) • Longer duration of typical symptomes of hyperglycaemia without ketosis. • Hyperglycaemia without typical symptomes discovered by screening • Following longer duration of typical symptomes of hyperglycaemia, in unconscious state with severe exsiccosis and hyperglycaemia, without ketosis but with severe increase of plasma osmolality = nonketotic hyperosmolar coma (Type 2 diabetes mellitus) The clinical picture of type 1 diabetes mellitus • • • • • • • • • • The patient cannot survive without insulin replacement (insulin dependent diabetes) At diagnosis the patients are mostly young, with a major peak between 12 and 15 years of age. But over 10% of diabetic subjects over 65 years require insulin. T1DM can be manifested at any age. T1DM usually presents acutely with hyperglycaemic symptomes (polyuria, polydipsia, weight loss) and tiredness. Nausea, vomiting and drowsiness usually denote impending ketoacidosis. Minor symptomes include cramps, blurred vision and superficial infections. Subtle abnormalities of insulin secretion and glucose tolerance can be detected during the prediabetic phase. In this phase antibodies against beta cell antigens are found (ICA, GADA, anti-IA2). Some T1DM patients experience a temporary remission after starting the insulin treatment: „honeymoon period”. Good glycaemic control with low insulin doses are characteristic for this period. This is due to the correction of hyperglycaemia, as hyperglycaemia itself directly damages the beta-cells („glucotoxicity”). Remisson ends when continuing autoimmune damage has dstroyed a critical mass of beta-cells. Long standing T1DM patients are susceptible to microvascular complications specific to diabetes, and to nospecific macrovascular disease. Mortality in T1DM is increased 4- to 7-fold over the matched nondiabetic population. The main causes of death are the nephropathy and coronary heart disease. A proportion of T1DM patients survive without significant complications for many years. Symptomes of T1DM Major symptomes Thirst Polyuria Weight loss Fatigue Minor symptomes Cramps Constipation Blurred vision Candidiasis Skin sepsis Features of ketoacidosis Nausea Vomiting Drowsiness Abdominal pain • • • • • • • • • • • • • The clinical picture of type 2 diabetes mellitus • T2DM denotes diabetic patients who can survive long term without insulin replacement, although many recieve insulin to improve their glycaemic control. • Prevalence if T2DM is about 2-3%, but is extremely common in certain communities (50% of pima indians in the USA). • Patients are mostly older and obese and present with insidious hyperglycaemic symptomes. Many cases are diagnosed incidentally or because of the presence of diabetic complications. • Specific microvascular complications are less common in T2DM compared to T1DM. However retinopathy (especially with maculopathy rather than proliferative changes), nephropathy and neuropathy all occur. • T2DM carries a high risk of large vessel atherosclerosis, commonly associated with hypertension, hyperlipidaemia (especially hypertriglyceridaemia) and obesity. Myocardial infarction is also common and accounts for 60% of deaths. • T2DM is not „mild diabetes”: overall mortality is increased 2-3 fold and life expectancy reduced by 5-10 years compared to the nondiabetic population. Some important statistics concerning T2DM • Very common - 75% of all diabetic patients • Disease of ageing - most patients are over 60 years of age • Obesity common - two thirds are overweight • Genetic factors - 40% of the patients have family history of T2DM • Male predominance - 3:2 male excess Modes of presentation of T2DM • • • • • Diabetic symptomes 53% Incidental finding (usually glycosuria) 29% Infections (candidiasis) 16% Complications 2% Screening in high risk population (obesity, hypertension, hyperlipidaemia, CHD, CVD, periferal arterial occlusive disease) ?% Causes of mortality in T1DM and T2DM (1971) T1DM • • • • • • • Coronary heart diseases Cerebrovsac. diasease Nephropathy Diabetic coma Malignancy Infections Others 15 3 55 4 0 10 13 T2DM 58 12 3 1 11 4 11 Characteristics of the metabolic syndrome • • • • • • • • • • Insulin resistance Hyperinsulinaemia Central obesity Glucose intolerance and T2DM Hypertension Dyslipidaemia (elevated triglyceride and decreased HDL cholesterol) Abnormal endothelial functions Procoagulant state Accelerated arteriosclerosis Hyperuricaemia Targets for control of diabetes mellitus low risk at risk macrovasc. high risk macro- and microvascular • HbA1c% <= 6,5 >6,5 >7,5 • Blood sugar level (mmol/l) Fasting <= 6,0 >6,0 Postprandial < 7,5 => 7,5 =>7,0 > 9,0 The main pathogenetic mechanisms in diabetes mellitus • No insulin secretion, all insulin producing beta-cells are destructed (T1DM) • Beta cell-failure: lacked first phase insulin release, delayed and exaggereted second phase insulin release (T2DM) • Insulin resistance (T2DM) Treatment of diabetes mellitus • • • • Diet Physical exercise Peroral antidiabetic drugs Insulin Aims of diet • In T1DM: fitting the carbohydrate intake and absorption with the insulin absorption from the injection site (the latter is not physiologic, as it is not given into the portal vein). Maintain the ideal body weight. • In T2DM: regain and maintain the ideal body weight (this will decrease the insulin resistance). Fitting the absorption of carbohydrates to the abnormal insulin secretion. Aims of physical exercise • In T1DM: maintenance of the patient’s fitness. Elimination of the „down phenomenon” in the morning and in the afternoon. • In T2DM: regain of ideal body weight. Decrease of insulin resistance. Transformation of T2DM to IGT/IFG; transformation of IGT/IFG to normal glucose tolerance. Aims of peroral antidiabetic drug treatment • In T1DM: delay of carbohydrate absorption can help the accomodation to the slow absorption of the exogenous insulin from the injection site (alpha glucosidase inhibitor) • In T2DM: improvement of insulin sensitivity (biguanid – metformin, PPAR-gamma agonists thiazolidinedions – rosiglitazon); increase of insulin secretion (sulphonylureas); delay of carbohydrate absorption (alpha-glucosidase inhibitor) Basics of nutritional treatment (diet) of diabetes mellitus • Adequate energy input: • In case of normal BMI, the energy input and output must be in balance, that is equal. Total energy need depends on the work load and the body weight or height of the patient. • In case of overweight (obesity) the energy input must be lower than the output till the patient reaches the ideal body weight. • The estimation of energy need: 1. (for example) the energy need of light work in a man with 168 cm height and in a woman with 164 cm height is about 2000 kcal/day. • The estimation of energy need: 2. Age activity 24 hour energy expenditure Men 18-30 /(weightx0,063)+2,896/ 1,55 (light) 31-60 /(weightx0,048)+3,653/ x 1,79 (moderate) = >60 /weightx0,040)+2,459/ 2,10 (heavy) X Women 18-30 /(weightx0,062)+2,036/ 31-60 /(weightx0,034)+3,538/ x >60 /(weightx0,038)+2,755/ 1,56 (light) 1,64 (moderate) = 1,82 (heavy) X Basal metabolic rate x physical activity multiplayer = 24 hour energy expenditure One has to know: energy contetnt of carbohydrate is 4 kcal/g; that is of fat is 9 kcal/g; that is of protein 4 kcal/g. Adequate composition of diet • Carbohydrate • Protein • Fat 55-60% 10-15% < 30% • Encourage complex, high fibre carbohydrates (dried beans, lentils, pas, oats, barly, wholegrain cereals, green leafy and root vegetables) and limit sucrose (<25 g added, <50 g total • Saturated fats <10% of total energy intake; ecourage MUFA (olive oil, rapeseed oil); cholesterol <250 mg/day (less if dyslipidaemia) • Limit salt intake (<6 g/day); limit alcohol intake; avoid „diabetic foods” Frequency of meals • Depends on the form of treatment • For example if diet only - three meals/day if diet + SU - five meals/day if insulin - 5-6 meals/day • 3 main meals + 2-3 snacks • Breakfast 45g carbohydrate • Diner 65g carbohydrate • Supper 60 g carbohydrate • Snacks 2 – 3x 15 g • Sum: ~200 g carbohydrate (800 kcal) Glycemic index • The glycemic responses vary considerably, even between different foods that contain the same amount of carbohydrate. • This difference are related to many factors: content of fibers, fat and protein, which may affect gut motility and intestine absorption; the amount of resistanr (indigestible) starch; the physical form of the food; and so on. Area under the glycemic curve after test food Glycemic index (%)= Area under the glycemic curve after glucose Basics of physical exercise as treatment of T2DM (1) • Changes of lifestyle in newly industrialised and developing countries have benn followed by dramatic increase in the incidence and prevalence of T2DM. • One of the most important factors in this respect are the physical inactivity, the sedentary lifestyle and the excessive energy intake with consume of meals having high fat and concentrated refined carbohydrate content. • „Coca-colonisation”. „Ugly change of the phenotype of human being.” Epidemiological data suggesting that exercise reduces the incidence of T2DM: • The University of Pennsylvania Alumni Study: 5990 male alumni. T2DM developed in a total of 202 of them during 98.524 person years of follow up from 1962 to 1976. Leisure time physical activity (in kcal) was to be inversely related to the developement of diabetes. For each 500 kcal increment in energy expenditure reduced the age adjusted risk of T2DM by 6%. Basics of physical exercise as treatment of T2DM (2) • The Nurses Health Study: 87.253 woman, aged 34-59 years, free from diabetes, CVD and cancer. During 8 years of follow up 1303 participants became diabetic. Women who engaged in vigorous exercise at least once a week had an age adjusted relative risk for diabetes of 0,67 (highly significant decrease of risk) compared to women who did not exercise weekly. • Physicians Health Study, Malta Study, Honolulu Heart program gave the same results. • Malmö Study: 181 subjects with IGT and 41 subjects with early T2DM. Five years protocol. In 50% of IGT patients with lifestyle change the carbohydrate tolerance reverted to normal. The accumulated incidence of diabetes was 16%. Among IGT patients in the non-intervention group th incidence of T2DM was 28,6%. • Examples of moderate amount of activity (activity that uses ~150 kcal of energy/day or 1000 kcal/week: waswhing and waxing a car for 45-60 min., washing windows or floors for 45-60 min., playing volleyball for 45 min., gardening for 35-40 min., walking 2,8 km in 35 min., bicycling 8 km in 30 min., dancing (fast) for 30 min., stair climbing for 15 min. Peroral antidiabetic drugs (1) Sulphonylureas • Enhance the insulin release from the pancreatic beta-cell. • The drug closes the ATP-dependent K channel in beta-cell, this is followed the depolarisation of the cell membrane followed by the opening of the Ca channel. The latter is the stimulus of insulin release. • Hypoglycaemia can be induced by sulphonylureas. • Primary and secondary sulphonylurea resistance: ~20 – 20% • Only for treatment of T2DM • Glibenclamid, glipizid, gliklazid, glimepirid • Gilemal, Minidiab, Diaprel, Amaryl • Newer very short acting drugs - glinides (Novonorm, Starlix) originatig from the non-sulphonyl root of glibenclamid. = postprandial blood glucose regulators. To be taken at the start of the meal. Peroral antidiabetic drugs 2. Biguanides • Improve insulin sensitivity in the liver, enhance insulin independent glucose disposal (muscles) • Weight loss can be induced by biguanides. • Beneficial effect on plasma lipids. • Lactic acidosis can be induced (avoid alcohol, feverish diseases, renal-, liver insufficiency, left heart failure, x-ray with contrast material). • No hypoglycaemia. • Only in T2DM • Contraindicated in MIDD. • Only metformin (Merckformin, Adimet, Metfogamma) Peroral antidiabetic drugs 3. Alpha-glucosidase inhibitors. • Inhibition and delay of the digestion of disaccharides, dextrin, starches in the gut. • Decrease postprandial hyperglycaemia. • Bacterial decomposition of undigested carbohydrates causes the side effects: flatulence, abdominal distension, diarrhoea. • Mainly in T2DM but can be used in T1DM, too. • Glukobay. Peroral antidibetic drugs 4. Insulin sensitisers? • Peroxysoma proliferator activated receptor agonists (PPAR-gamma agonists) • Thiazolidindions or glitazons • They decrease glucose and insulin levels, that is improve insulin sensitivity. • They decrease triglyceride level in the serum and hepatic and adipose tissue NEFA production. • Side effects: haemodilution, oedema formation, liver failure, heart failure • Rosiglitazon - Avandia Treatment scheme of T2DM 1. step: diet and increase of physical activity 2. step: reinforce diet and physical exercise 3. step: reinforce diet and physical exercise 4. step: diet, physical exercise + metformin and/or alpha glucosidase inhibitor 5. step: as 4. step + PPAR-gamma agonist (?) 6. step: as 4. step + sulphonylurea 7. step: insulin Basics of insulin therapy 1. Estimation of insulin dose: • Basal insulin requirement 40% • Prandial insulin requirement 60% • Prandial insulin dose must be the highest in the morning (because of the relative insulin resistency) • Endogeneous insulin secretion in a nondiabetic adult is about 30 U/day • The daily insulin requirement in diabetes mellitus is higher, than the endogeneous insulin secretion in a healthy human being, becuse in the former cases the insulin is not administered intraportally. Basics of insulin therapy 2. Example 1. • The insulin need is 40 U/day • Basal 16 U/day (40%); prandial 24 (60%) • 12 U is necessary before breakfast, 6 U is necessary before lunch, 6 U is necessary before diner and 16 U necessary at bedtime. The premeal insulins are fast acting, the bedtime insulin is intermediary acting. During daytime the basal insulin secretion is replaced by the delayed absorption of fast acting insulin. Example 2. • 40 U of insulin is the requirement • 28 U necessary before breakfast + 12 U is necessary before the evening meal. • The insulin is premixed, containing 30% of fast acting and 70% of intermediary acting component. • At lunchtime, the peak level of the intermediary acting component gives the insulin for the lunch. Basics of insulin therapy 3. The insulins available are divided into: Insulin starts working after (minutes) 10-20 30 time of strongest length of action (h) action (h) 1-2 1-4 4 <8 Ultrashort Short acting Intermediate acting Long acting 30 - 120 240 4 -12 10 -12 <24 <36 Basics of insulin therapy 4. The name of insulins available in Hungary • Ultra short acting (analogue): Humalog and Novorapid • Short acting (human insulin): Humulin R and Actrapid • Intermediate acting (human insulin): Humulin N and Insulatard • Long acting (human insulin): Humulin L and Ultratard • Long acting (analogue): Lantus Basics of insulin therapy 5. Treatment schemes with insulin. Intensive conservative regimens • 3x short actin insulin (before the main meals) +1x intermediate acting insulin (at bedtime) • 3x ultrashort acting insulin (before the main meals) + 2x intermediate acting insulin (in the morning and at bedtime) Conservative regimens • 2x premixed insulin (before breakfast and dinner) Insulin pump therapy • With ultra short acting insulin • Continously pumped low dose of the ultrashort acting insulin subcutaneously (for replacement of basic insulin secretion) with increased velocity of infusion before meals (for replacement of prandial insulin secretion) Laboratory methods for the evaluation of the control of the patient’s diabetes mellitus • Fasting and postprandial (1,5 – 2 hours after meal) blood sugar level • Glycated hemoglobins (HbA1c) control of diabetes during the previous 3 months • Blood lipid profile • Urinary albumin output (microalbuminuria) Basics of treatment of diabetic ketoacidosis and nonketotic hyperosmolar coma • Absolute deficiency of the body for water and electrolytes (NaCl and K) • Absolute deficiency of insulin • Absolute deficiency of glucose • Absolute deficiency of glycogen stores • • • • 1000 ml of physiologic saline hourly 4-8 U short acting insulin /hour iv (with a pump) 10 ml of 10% KCl in intravenous infusion /hour 5% glucose infusion if blood sugar level decreases to 10 mmol/l