DIABETES MELLITUS Dr. Hasan Fahmawi, MRCP(UK), FRCP(Edin)

• DM is a clinical syndrome characterized by an increase in plasma blood glucose.

• Type 1 is generally considered to result from autoimmune destruction of beta pancreatic cells, leading to marked insulin deficiency. It associated with insulin antibodies, anti-GAD(Glutamic Acid Decarboxylase) antibodies, anti ZnTB antibodies which increase sensitivity to 92%.

• Type 2 is characterised by reduced sensitivity to the action of insulin and inability to produce sufficient insulin to overcome this insulin resistance. Acute hyperglycaemia cause symptoms, metabolic derangement and frequent hospital admissions. Chronic hyperglycaemia is responsible for diabetic specific microvascular complications affecting the eyes, kidneys and feet (neuropathy)

• Less severe hyperglycaemia is called impaired glucose tolerance and associated with an increased risk of large vessel disease. (Atheroma leading to MI. stroke and PVD)

• Incidence of DM is rising world wide, about 10% of the population in 2015, (415 millions), which is due to greater longevity, sedentary life style, unsatisfactory diet, increasing urbanization and economic development. Type 2 DM is seen now in children and adolescents particularly in some ethnic groups as Hispanics, none Hispanic blacks and Asian Indians.

• Type 1 diabetes is more common in Caucasian, and more people are diagnosed in winter months.

• It causes 5 million deaths, costs 673 billions $, and 12% of total health care expenditure.

• Insulin is the primary regulator of glucose metabolism and storage, and is secreted to the portal circulation. It is anabolic hormone increasing carbohydrate, lipid and protein synthesis, but decreasing gluconeogenesis, glycogenolysis, lipolysis, and protein degradation.

• Blood glucose homeostasis is important for brain supply.

• GLUT4, Glucose Transporter.

Symptoms of hyperglycaemia

• Thirst, dry mouth. • Polyuria, nocturia. • Tiredness, fatigue and lethargy. • Weight loss. • Blurring vision. • Pruritus vulvae, balanitis.(genital candidiasis). • Nausea. • Headache. • Hyperphagia. (predilection for sweet foods) • Mood changes, irritability, difficulty in concentration, apathy.

Investigations

• Urine glucose warrants FBS due to renal glycosuria in lower renal threshold, which is common in pregnancy and young people.

• Blood glucose relies on enzymatic reaction(glucose oxidase) and is cheap, and it can be measured with testing sticks that are read with

• a portable electronic meters. These are used for capillary testing to monitor treatment ? and to avoid hypoglycaemia.

• Blood glucose is lower in venous than arterial or capillary (fingerpick)

• Blood- whole blood concentration are lower than plasma concentration.

Interstitial Glucose

• Interstitial Continuous Glucose monitoring (CGM), uses a tiny sensor implanted under the skin, which is kept in place for 2 wks. Before being replaced.

• It provides real- time measurements of glucose every 1-5 minutes. Alarms can be incorporated to warn patient about hypoglycaemia.

• Patient must check glucose level before driving or changing therapy.

Glycated Hb

• It provide an accurate and objective measure of glycaemic control over wks. or months, arise of 11 mmol/mol in Hb A1c corresponds to

• an approximate average increase of 2mmol/L (36mg/dL). • It is more sensitive to glycaemic control in the month before measurement. • Diminished in, anaemia, haemogobinopathies, uraemia and pregnancy. • Islets antibodies consist of antibodies to Insulin, Glutamic Acid

Decarboxylase (GAD). Auto-immune DM, Stiff man syndrome. • Urine protein standard dipstick detects levels above 300mg/L, but smaller

amounts (microalbuminuria) can only be measured by using specific albumin dipsticks or quantitative biochemical tests, in the absence of infection it indicates diabetic nephropathy and/or increased macrovascular disease.

Diagnosis

• DM- microvascular complications

• Pre-diabetic-carry negligible risk of microvascular complications but at increased risk of developing DM. continuous risk of developing atheroma of large conduit blood vessels, causing CVD, MI, Stroke and PVD (macrovascular complications).

• WHO advocated the use of glycated Hb to diagnose DM, provided the patient has symptoms, HbA1c equal or above 48 mmol/mol is diagnostic of DM, but it should not be used in someone with short history, or severe symptomatic hyperglycaemia, then FBS is needed.

• When patient is a symptomatic and another confirmatory test is needed we use the same one.

• Pre-diabetic can be classified in to, impaired fasting glucose(IFG) and impaired glucose tolerance test (IGT). Patients must be informed of the risk of developing DM, given advice about life style modifications as diabetics, aggressive treatment of hypertension, dyslipidaemia and stopping smoking.

• Hb A1c for pre-diabetic is less clear.

Stress Hyperglycaemia

• In some people(especially those with pre-existing low insulin or low beta cell mass, an abnormal blood glucose is observed in acute severe illness, such as infection or MI. This (stress hyperglycaemia) is a consequence of hormones, such as cortisol and catecholamines. antagonizing the action of insulin and thereby increasing insulin resistance, those patients have increased risk of developing type2 DM in the future years.

• In DM, RFT, electrolytes, Lipid profile, LFT and TFT must be done.

LADA Latent Auto-immune Diabetes of Adulthood. • Insidious onset of autoimmune diabetes, with islets auto-antibodies

in a high titer(usually GAD antibodies without rapid progression to insulin therapy), at the beginning they are managed as type2 DM.

• Insulin Resistance syndrome or the Metabolic Syndrome.

• Some people develop DM at a young age, usually driven by insulin resistance due to obesity and ethnicity, old age might have more beta cell failure. The key feature is relative insulin deficiency, at diagnosis

• About 50% of beta cells are damaged with deposition of amyloid in the islets. Beta cell number is decreased but mass is the same, Glucagon secretion is increased, which may contribute to hyperglycaemia.

• Genetic factor is important in type2 DM, monozygotic twins concordance rate approach 100%. It is polygenic.

• Incidence low in Alaska natives at 5.5%, non-Hispanic whites 7.7%,

• Non-Hispanic blacks at 13% and at native Americans at 33%

• In old age think of Carcinoma of the pancrease as a cause.

Causes of DM • Pancreatic diseases, chronic pancreatitis, pancreatectomy, neoplastic

disease, cystic fibrosis, and haemochromatosis.

• Drugs, thiazides, steroids, and phenytoin.

• Hormone antagonists, thyrotoxicosis, acromegaly, Cushing syndrome, and Glucagonoma.

• Associated with genetic syndromes, Down’s, Klinefelter’s, Turners syndrome, DIDMOAD, Friedreich’s ataxia, and myotonic dystrophy.

• Genetic defect of insulin action, Lipodystrophies.

Monogenic DM

• Accounts for nearly 4% of diabetics diagnosed below the age of 30 years, the most common type is defect in insulin secretion. MODY.

• Autosomal dominant inheritance, it occurs below the age of 25years.

• High fasting blood glucose usually above 5.5 mmol, but normal post prandial response.

• Glucokinase mutation, MODY patients have a stable mild hyperglycaemia, with only slightly elevated HbA1c.

Management of DM

• The aim is to improve symptoms, and minimize the long term complications of micro- and macro-vascular complications.

• Life style adjustment, oral hypoglycaemic drugs, and insulin.

• Specialist diabetic clinics or primary care where facilities are available and staff are trained in diabetic care.-

Target

• FBS, 5-7 mmol/L

• Pre-meal value, 4-7 mmol/L

• 2 hours post meal value 4-8 mmol/L

• Hb A1c 6-7%, 42-53 mmol/ mol

• Capillary blood sugar ca be used to guide patients in their insulin dosing to manage exercise and infection.

• Any diabetic patient who is above 40 years is started on statin.

• Healthy eating, carbohydrates 50% of energy, not more than 10% sucrose

• Fats 35% of energy, saturated less than 10%

• Protein,10-15% daily.

• Salt no more than 6gm daily, 2gm Na.

• Exercise 150 min/wk, for moderate exercise or 75 min for vigorous intensity exercise.

• Driving patient awareness of hypoglycaemia is important, no more than one attack per year of severe hypoglycaemia, blood sugar should be over 5mmol/L, repeat every 2 hrs.

Drugs

• Biguanides – Metformin

• Sulphonylureals.

• Thiozolidinediones, TZD, pioglitazone, enhance the action of endogenous insulin, both directly and on adipose cells.

• Alpha- glucosidase inhibitors, delay carbohydrate absorption by inhibiting disaccharidases. Acarbose.

• Incretin-based therapies, incretin potentiates insulin secretion, but it is diminished in Type 2 DM. GLP-1 and GIP Gastric Inhibitory Peptide (incretins) are rapidly broken down , DPP-4 prevents breakdown and therefore enhance concentration of GLP-1, drugs are called Gliptins, Sitagliptin has no adverse CV effects, Saxagliptin has increased incidence of HF.

• GLP-1 receptor agonists resist the breakdown of DDP-4, given S/C. However they have a key advantage over DDP-4 inhibitors, because the GLP-1 activity achieved is, supra-physiological. It delays gastric emptying and, at the level of hypothalamus, decreases appetite.( Exenatide BID, and Exenatide modified- release once per wk., liraglutide daily and abiglutide once per wk.) Liraglutide when added to usual therapy improves CV outcome in high risk patients. They may cause nausea and all incretin-acting drugs are associated with an increased risk of pancreatitis..

• SGLT2 inhibitors, The Sodium and Glucose Transporter 2 inhibitors, dapagliflozin, empagliflozin .They carry 25% reduction in glucose reabsorption , Empaglifozin carries 35% reduction in CV mortality and hospital admissions.

• Diabetes and surgery- stop all oral drugs, start short acting insulin.

• Pancreatic and kidney transplant, Pancreatic cell transplant, artificial pancreas.

• Complications of DM.