Diabetes mellitusDM is characterized by elevated blood sugar levels due to absolute or relative lack of insulin.Type 1 diabetes - β-cell failure at outset ◦ Insulin dependentType 2 diabetes - Gradual β-cell deterioration ◦ Early stages: Diet and Oral agents ◦ Late-stage: Insulin therapy
Glycosylated hemoglobin Hb-A1cItis used to monitor the plasma glucose concentration over prolonged periods of time (4-6 weeks).Insulin secretion is promoted by: ◦ ↑ blood glucose levels ◦ ↑ amino acids ◦ GI hormones ◦ β-2 agonist: stimulates glycogenolysis release of glucagon
Insulin Insulin is a storage hormone: i. it promotes anabolism ii. inhibits catabolism of carbohydrates, fatty acids and protein. In the absence of insulin: i. most tissues cannot use glucose ii. fats/proteins are broken down to provide energy.
Mechanism of action:Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle.
Liver:1. Insulin increase the storage of glucose as glycogen in the liver. ◦ It inserts the GLUT-2 glucose transport molecule in the cell membrane.1. It inhibits gluconeogenesis – thus significantly ↓ glucose output by the liver.2. It decrease the protein catabolism.
Muscle :1. Insulin stimulates the glycogen synthesis and protein synthesis. ◦ Glucose transport into the cells is facilitated by GLUT-4 into the cell membrane.1. It inhibits the protein catabolism.
Signs and symptomsThe classic symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.
Diabetic emergenciesPeople (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.
Complicationstypically develop after many years (10– 20).damage to blood vessels.Diabetes doubles the risk of cardiovascular disease, ”macrovascular" diseases, (related to atherosclerosis of larger arteries) include ischemic heart disease (angina and myocardial infarction), stroke and peripheral vascular disease.
Diabetes also damages the capillaries(causes microangiopathy). Diabetic retinopathy, which affects bloodvessel formation in the retina of the eye,can lead to visual symptoms, reducedvision, and potentially blindness.Diabetic nephropathy, the impact ofdiabetes on the kidneys, can lead toscarring changes in the kidney tissue, lossof small or progressively larger amounts ofprotein in the urine, and eventually chronickidney disease requiring dialysis.
Diabetic neuropathy is the impact ofdiabetes on the nervous system, mostcommonly causing numbness, tingling andpain in the feet and also increasing the riskof skin damage due to altered sensation.Together with vascular disease in the legs,neuropathy contributes to the risk ofdiabetes-related foot problems (such asdiabetic foot ulcers) that can be difficult totreat and occasionally require amputation.
Insulin Adipose tissue : 1. Insulin facilitates the storage of triglyceride by: i. activating plasma lipoprotein lipase ii. inhibiting intracellular lipolysis. 2. It increase the glucose uptake by GLUT-4 insertion into the cell membrane.
Effect of insulin on glucose uptake and metabolism glycolysis
Insulin is a 51 AA peptideNot active orally.Insulin is inactivated by insulinase (insulin transhydrogenase ) found mainly in liver and kidney.Dose reduced in renal insufficiencySources of Insulin : ◦ Beef pancreas / Pork pancreas ◦ Human insulin: recombinant DNA origin
Human Insulin:Do not contain measurable amounts of proinsulin or contaminants.Diminished antibodyLess allergic reactionsLess lipodystrophyPreferred in gestational diabetes
Insulin preparations:A.Rapid acting insulin: Lispro, Aspart and GlulisineB.Short acting insulin: Regular (crystalline)C. Intermediate acting insulin: NPH (isophane) and Lente (insulin zinc)D. Long acting insulin: Protamine—zinc , Ultralente, Detimir and Glargine
Insulin Duration Route FeaturesLispro 3 – 5 hrs I.V or S.C Onset within 15 minutesRapid actingRegular 7 – 10 hrs I.V or S.C common(crystalline)Short actingNPH 16 – 20 hrs S.C NPH can mix(Neutral protamine with regularhagedorn)Intermediate actingUltralente 24 – 30 hrs S.C Basal levelLong acting
Adverse effects of InsulinHypoglycemiaAllergicreactionsLipodystrophyOthers includes ◦ Seizures ◦ Coma
Oral Anti-diabetic drugsMechanisms to reduce blood sugar1.Stimulation of pancreatic insulin release – Sulfonylureas, Meglitinide2.Reduce the bio-synthesis of glucose in liver – Biguanides (Metformin)3.Increase the sensitivity of target cells to insulin -- Thiazolidinediones4.Retard the absorption of sugars from the GI tract – Acarbose, Miglitol
Duration of action ofsome oralhypoglycemic agents.
Major actions of the principal oral antidiabetic drugs used to treat type 2 diabetes
A. Alpha-Glucosidase Inhibitors: Acarbose (Glucobay) , Miglitol (Glyset) 1. They inhibit α-glucosidase which converts dietary starch and complex carbohydrates into simple sugars 2. It reduces absorption of glucose after meals. The main side effects includes flatulence and diarrhea.
B. Insulin secretagogues1. Sulfonylureas : First generation : ◦ Acetohexamide ◦ Chlorpropamide ◦ Tolbutamide ◦ Tolazamide Second generation : Glipizide, Glyburide more potent more efficacious fewer adverse effects. Third generation : Glimiperide
Mechanism of Action:1)Stimulation of insulin release from the β cells of the pancreas by blocking the ATP- sensitive K+ channels, resulting in depolarization and Ca2+ influx2)reduction in hepatic glucose production3)increase in peripheral insulin sensitivity.
Sulfonylureas: Adverse effects :HypoglycemiaCholestatic jaundiceWeight gainCross placenta – fetal hypoglycemia.Chlorpropamide : ◦ It can cause water retention by ↑ release of ADH (SIADH) ◦ Disulfiram-like reaction with alcohol.
2. Glinides: Repaglinide, NateglinideMore rapidly acting insulin enhancers and shorter duration than sulfonylurea.These are insulin secretagogues that act by blocking ATP-dependent K+ channels.This leads to increased insulin secretion by pancreatic β-cells.Hypoglycemia is the common adverse effect.Less weight gain
Repaglinide, NateglinideThe drug has minimal renal excretion thus useful in patients with DM and impaired renal function. It is designed to be taken with each meal to stimulate insulin release with meal. If a meal is skipped, so is the repaglinide.
C. Insulin sensitizers 1. Biguanides 2. Thiazolidinediones1. Biguanides (Metformin): ◦ Inhibits glucose output (gluconeogenesis). ◦ It increase the sensitivity of liver and muscle to insulin. (increase uptake of glucose) ◦ Does not promote insulin secretion. ◦ It causes modest weight loss.
Biguanides: Metformin (Glucophage) ◦ It does not cause hypoglycemia. ◦ It produces a significant ↓ TG and LDL, and ↑HDL.There is a serious concern about lactic acidosis especially in patients with kidney disease.
2. Thiazolidinediones (glitazones)Enhance glucose and lipid metabolism through action on Peroxisome Proliferator Activated Receptor (PPAR–γ)Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters.E.g. :Pioglitazone Actos,Rosiglitazone Avandia: EMA recommended in Sep 2010 to be suspended from the EU market due to elevated cardiovascular risks
Thiazolidinediones:Beneficial effects on serum lipid; ↓TG and ↑HDL.Troglitazone(Rezulin), was withdrawn in 1990s from the market due to an increased incidence of drug-induced hepatitis.The main side effect of all thiazolidinediones is water retention, leading to edema .
Agent Mechanism Site of action Main advantages Main side effects Stimulating insulin production by •Effective •HypoglycemiaSulfonylureas inhibiting the KATP Pancreatic beta cells •Inexpensive •Weight gain channel •GI symptoms, •May result in mild including Decreases insulin weight loss diarrhea, nausea, Metformin resistance Liver •Does not cause abdominal pain hypoglycemia •Lactic acidosis •Metallic taste •GI symptoms, including Reduces intestinal diarrhea, Acarbose glucose absorption GI tract •Low risk abdominal cramping, flatulence Reduce insulinThiazolidinedion resistance by Fat, muscle Hepatoxicity es activating PPAR-γ
A. Incretins• Glucagon-like peptide-1 (GLP-1)• Gastric inhibitory peptide (GIP)• Released from the gut
• Function of incretins: 1. augment glucose-dependent insulin secretion after a meal. 2. They also slow the rate of absorption of nutrients into the blood stream by: 1. reducing gastric emptying 2. may directly reduce food intake 3. They inhibit glucagon release from the alpha cells of the Islets of Langerhans.
Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4). DPP-4GIP Inactive productsGLP-1
A. Incretin Mimetics: • Exenatide (Byetta) • Liraglutide (Victosa): long duration of action approved in 2010 • GLP-1 analogs. • improves glucose-dependent insulin secretion • slows gastric emptying time • decreases food intake • decreases postprandial glucagon secretion • promotes β-cell proliferation. • Consequently, weight gain and postprandial hyperglycemia are reduced, and HbA1c levels decline. • Exenatide is administered subcutaneously.
Exenatide : Short duration of action.Use:as an adjunct to therapy in patients with Type 2 diabetes who have failed to achieve adequate glycemic control on a sulfonylurea, metformin, glitazone, or combination thereof.Adverse effects:Nausea, vomiting, and diarrhea.
Sitagliptin(Januvia) FDA approved Oct 2006Vildagliptin (Galvus) EU Approved 2008Saxagliptin (Onglyza) FDA Approved July 2009Linagliptin (Tradjenta) FDA Approved May 2, 2011B. Dipeptidyl Peptidase-IV Inhibitors
Sitagliptin (Januvia)Mechanism of action• Sitagliptin inhibits the enzyme DPP-IV, which is responsible for the inactivation of incretin hormones.• Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion of glucagon.• Use: – as monotherapy or in combination with a sulfonylurea, metformin or a glitazone.
Pharmacokinetics and fate• Well absorbed after oral administration.• Food does not affect the extent of absorption.• The majority excreted unchanged in the urine.• Dosage adjustments are recommended for patients with renal dysfunction.Adverse effects• Nasopharyngitis and headache.
Synthetic Amylin Analog: Pramlintide (SYMLIN): Amylin:37-aa peptide produced by beta cells and co-secreted with insulin.Effects: 1. Inhibits glucagon secretion 2. delay gastric emptying 3. suppress appetite
Pramlintide (SYMLIN):•indicated as an adjunct to mealtime insulin therapy in patients with Type 1 or Type 2 diabetes.•Effects: - delays gastric emptying - decreases postprandial glucagon secretion - improves satiety
•Administration of Pramlintide: •subcutaneous injection •injected immediately prior to meals.•When pramlintide is initiated, the dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia.•Adverse effects are mainly gastrointestinal and consist of nausea, anorexia, and vomiting.
Agents that increase blood glucose (hyperglycemics)Glucagon: UsesA.firstaid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally.B.treatment of overdose with beta blockers ◦ It has positive inotropic action and chronotropic action on the heart. ◦ It acts by stimulation of glucagon receptors and not through beta 1 receptors.
Diazoxide Diazoxide is a nondiuretic thiazide that promptly increases blood glucose levels by direct inhibition of insulin secretion. Diazoxide is useful in cases of insulinoma or leucine- sensitive hypoglycemia. Diazoxide may cause sodium retention, gastrointestinal irritation, and changes in circulating white blood cells.