Diabetes Mellitus Fifth Stage-Medicine Dr. Sarbast Fakhradin MBChB, MSc Diabetes Care & Management

Comprehensive diabetes care of type 2 DM

Patient education & follow up: DAFNE & DESMOND It is essential that people with diabetes understand their disorder and learn to handle all aspects of their management & educating patients about diabetes complications. Carry a diabetic card stating their name and address. Driving

Patient education & follow up: DAFNE & DESMOND Blood glucose monitoring; Target Preprandial capillary plasma glucose (70-130 mg/dl) Target postprandial capillary plasma glucose (< 180 mg/dl) A. Treatment with insulin; Regular BG monitoring should be performed by all patients to adjust the insulin dose and detect hypoglycaemia Daily pre-prandial and bedtime measurements are usually recommended

Treatment with oral hypoglycemic agents; BG monitoring is optional in many patients with stable type 2 diabetes. Monitoring is most useful in patients taking sulphonylureas, during intercurrent illness and prescription of corticosteroids, and during changes in therapy. Lower limbs & feet Blood pressure < 130/80 Smoking & alcohol Hypoglycemic episodes. Psychological support Target Lipid profile: Cholesterol< 200mg/dl, LDL < 100 mg/dl, TG < 150 mg/dl HDL> 40 mg/dl.

Lifestyle modification 1. Healthy diet 2. Regular Exercise: in the form of walking, gardening, swimming or cycling, approximately 30 minutes daily, as this improves insulin sensitivity and the lipid profile and lowers blood pressure. 3. Stop smoking 4. Reduce/stop alcohol intake 5. Salt: reduce sodium intake to no more than 6 g daily.

The glycaemic index (GI) of a carbohydrate-containing food is a measure of the change in blood glucose following its ingestion. Consumption of foods with a low GI is encouraged. All the CHO prescribed should be taken in the form of starches and other complex sugars. 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. Low-calorie and sugar-free drinks are useful for patients with diabetes. These drinks usually contain non-nutritive sweeteners. Many 'diabetic foods' contain sorbitol, are expensive and high in calories, and may cause gastrointestinal side-effects. As a result, these foods are not recommended as part of the diabetic diet.

Recommended composition of diet for people with diabetes: CHO 40-65% Fat < 35% ( saturated <10%) Protein 10-15% Fruit/Vegetable 5 portions daily

Anti-Diabetic Medications Oral Agents: 1. Biguanides (Metformin) 2. Insulin Secretagogues – Sulphonylureas (Gliclazide) 3.Insulin Secretagogues – Non-sulphonylureas (Repaglinide) 4. DPP4 inhibitor (Sitagliptin) 5. α-glucosidase inhibitors (Acarbose) 6. Thiazolidinediones (TZDs) (Pioglitazone) Injections: 1. Insulin 2. GLP-1 agonist (Incretin mimetic) Exenatide & Liraglutide

Biguanides (Metformin) First drug of choice for obese patients in whom strict dieting has failed to control type 2 diabetes. Insulin sensitivity and peripheral glucose uptake are increased, Impairs glucose absorption by the gut and inhibits hepatic gluconeogenesis It does not increase insulin secretion and seldom causes hypoglycaemia. Metformin is given with food.

Biguanides (Metformin) Glucose-lowering effect of metformin is synergistic with that of sulphonylureas. Improves lipid profiles & reduces risk of CA. SE: Dyspepsia, Risk of lactic acidosis: contraindicated in patients with impaired renal or hepatic function, drinking alcohol in excess, hypoxia, & shock. Not contraindicated in pregnancy.

SULPHONYLUREAS Mainly for people with type 2 diabetes who are not overly obese. First Generation: Tolbutamide (well tolerated, short acting, useful in elderly), Chlorpropamide Very long acting (up to 60 hours), avoid in elderly. Second generation: Glibenclamide, Gliclazide, Glimepiride, Glipizide. Glibenclamide is prone to induce severe hypoglycaemia (avoid in the elderly) Principally stimulate production of insulin, may reduce glucagon levels.

SULPHONYLUREAS SUs can cause hypoglycaemia and their use should therefore be closely monitored in the elderly & in those with nephropathy. Several drugs can potentiate their hypoglycaemic effect (e.g. salicylates, phenylbutazone and antifungal agents) SE: Hypoglycemia, increased appetite and weight gain, skin rashes (hypersensitivity) and G.I. Disturbances, cholestatic Jaundice, blood dyscrasia. Feature of disulfiram- like reaction occur in some patients after taking alcohol. Occasionally chlorpropamide can induce (SIADH).

Meglitinides - prandial glucose regulators Repaglinide, Nateglinide Stimulates insulin release (rapid and short acting) Better control of postprandial hyperglycaemia Take before meals. It is less likely to cause hypoglycaemia than sulphonylureas.

Alpha-glucosidase inhibitors (Acarbose) Carbohydrate digestion in the small intestine is slowed down by selectively inhibiting disaccharidases Glucose is not absorbed into the bloodstream so quickly. SE: Bloating, flatulence, diarrhoea and abdominal pain, especially upon initial treatment.

Thiazolidinediones (pioglitazone) Bind and activate peroxisome proliferator-activated receptor-γ (PPARγ agonists). Reduced insulin resistance and decreased insulin levels insulin concentrations are not increased & hypoglycemia is not a problem. Fat redistribute from the abdominal stores and into subcutaneous depots. However, body weight and total body fat are increased. Pioglitazone may reduce myocardial infarctions and strokes (improvement in endothelial function), but increase the risk of HF?

Thiazolidinediones (pioglitazone) SE: sodium and fluid retention, which is aggravated if they are combined with insulin, upper limb fractures. TZDs must be avoided in patients with cardiac failure, hepatic impairment or severe renal insufficiency. Increase LDL (non-atherogenic form?), increased HDL, lowered FFA, lowered triglycerides.

Oral hypoglycaemics  Rate of carbohydrate breakdown/ absorption -glucosidase inhibitors  Insulin secretion Sulfonylureas/ meglitinides Biguanides Thiazolidinediones  Glucose output  Insulin resistance  Insulin resistance

Mechanisms of glucose-stimulated insulin secretion

Incretin-based therapies The secretion of insulin in response to a rise in blood glucose is greater when glucose is given by mouth than by intravenous infusion. In part this is caused by secretion of gut hormones, or incretins (Glucagon-like peptide (GLP-1), which potentiate glucose-induced insulin secretion. GLP-1 suppresses glucagon secretion, delays gastric emptying, reduces appetite and encourages weight loss.

Incretin-based therapies (Cont.) They improve postprandial glucose excursions and early satiety GLP-1 is rapidly degraded by the enzyme, dipeptidyl peptidase 4, inhibitors of this enzyme can be used to prolong its biological effect. The DPP-4 inhibitors or gliptins (sitagliptin, vildagliptin and saxagliptin) are oral agents which act in this manner.

Incretin-based therapies (Cont.) Exenatide & Liraglutide (SC injection) are Synthetic GLP-1 receptor antagonists with longer therapeutic action. They induce weight loss in most patients. SE: pancreatitis & GI disturbance. Incretin-based therapies are most useful in obese patients and can be used in combination with other oral anti-diabetic agents.

Insulin Insulin are either bovine or porcine, human insulin produced by recombinant DNA technology & protein engineering technique. In most countries, the insulin concentration in available formulations has been standardised at 100 U/mL. Plastic Syringe or pen injector. Insulin is usually given by the SC route, IV or IM routes. Rotation of injection sites is recommended to reduce insulin injection site damage.

Insulin (Cont.) It is removed mainly by the liver and also the kidneys; plasma insulin concentrations are elevated in patients with liver disease or renal failure. Absorption from the abdomen is faster than from thighs or upper arms and may be preferred for short- acting preparation. Insulin absorption may be influenced by insulin formulation, injection site, depth and volume of injection, skin temperature (warming), local massage and exercise.

Types of insulin Rapid-acting insulin – it begins to work about 5 minutes after injection, peaks in around 1 hour, and continue to work for 2-4 hours (Lispro, Aspart). Regular or Short-acting insulin – reach the bloodstream within 30 minutes after injection. It will peak anywhere from 2-3 hours after injection and will stay effective for around 3-6 hours. Intermediate-acting insulin (NPH) - reach the bloodstream within 2-4 hours after injection. It will stay effective for around 12-18 hours. Long-acting insulin (Glargin) this type of insulin will reach the bloodstream within 6-10 hours after injection and will stay effective for 20-27 hours. Premixed insulin

Insulin Side-effects: Hypoglycaemia Weight gain Peripheral oedema (insulin treatment causes salt and water retention in the short term) Insulin antibodies (animal insulins) Local allergy (rare) Lipodystrophy at injection sites

Insulin dosing regimens Most people require two or more injections of insulin daily. Once-daily injections rarely achieve satisfactory glycaemic control & are reserved either for some elderly patients or for those who retain substantial endogenous insulin secretion & have a low insulin requirement. Twice- daily mixtures of short- and intermediate acting insulin is a commonly used regimen. Basal-Bolus: A regimen of multiple injection of short- acting insulin before the main meals, with an appropriate dose of single daily intermediate- or long acting insulin. 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 (Sick Day rule)

Combined oral anti-diabetic therapy and insulin In patients with type 2 diabetes who are requiring increasing doses of oral anti-diabetic drugs, the introduction of a single dose of an intermediate- (e.g. isophane) or long-acting insulin analogue, administered at bedtime, may improve glycaemic control and delay the development of overt pancreatic β-cell failure. Insulin Pump Transplantation Surgery

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