diabetes-related foot problems

Insulin, Oral Hypoglycemic Drugs Insulin, Oral Hypoglycemic Drugs

Diabetes mellitus a heterogeneous group of syndromes all characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin

Fasting plasma glucose level ≥ 7.0 mmol/L Plasma glucose ≥ 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test. Symptoms of hyperglycemia and casual plasma glucose ≥ 11.1 mmol/L (200 mg/dL). Diagnosis

Classification: Insulin-dependent diabetes mellitus, IDDM Type 1(Insulin-dependent diabetes mellitus, IDDM): Lack of insulin. Non-insulin-dependent diabetes mellitus, NIDDM Type 2(Non-insulin-dependent diabetes mellitus, NIDDM): Cells resistance to insulin

Signs & symptoms: Very thirsty Feeling tired Using the toilet often to urinate Constant hunger High level of glucose in urine & in fasting blood

Harms (complications) ▲ Acute Diabetic ketoacidosis (DKA) Nonketotic hyperosmolar coma

Chronic Microvascular disease: impotence & poor wound healing Atherosclerosis : Strokes, coronary heart disease

Renal failure, retinal damage, nerve damage Renal failureretinal damagenerve damage Infective disease: Tuberculosis

Treatment 1.Dietary control (fixed time, fixed quantity, fixed ingredient) 2.Sensible exercise 3.MedicationsMedications

1. Insulin 1. Insulin Insulin 2. Oral hypoglycemic agents 2. Oral hypoglycemic agentsOral hypoglycemic agentsOral hypoglycemic agents

Treatment Type 1: Insulin must be injected or inhaled

Type 2: Food control, exercise, medicines (1) agents which increase insulin secretion;

(2) agents which increase the sensitivity of target organs to insulin; (3) agents which decrease glucose absorption (4) Insulin needed for patients with serious complications or an emergency.

Insulin ● Chemistry: 51 aa arranged in two chains (A & B) linked by disulfide bridges.51 aa arranged in two chains (A & B) linked ● Secretion: By βcells in pancreatic islet.

Degradation: Liver & kidney Endogenous: Liver (60 %) & kidney (35 %-40 %) Exogenous: Liver (35 %-40 %) & kidney (60 %) ● t1/2 in plasma: 3-5 min

Resource: 1.Animal insulin: from pancreas of beef and pork 2.Human insulin: gene recombination, high purity, iv

● Physiological & pharmacological actions 1.Sugar metabolism: Stimulates glucose uptake & use by cells; inhibits gluconeogenesis → blood sugar ↓

2. Fatty metabolism: Improves fatty acid transportation & fat anabolism; inhibits fat catabolism & fatty acid and acetone body generation

3. 3.Protein metabolism: Improves aa transportation & protein anabolism; inhibits protein catabolism & aa utilization in liver

Insulin

4. Potassium : Stimulates K + entering cells→blood K + ↓ Physiological & pharmacological actions

5. Long-term action: Improves or inhibits the synthesis of some enzymes.

Mechanism of its action ＊ Insulin receptor in cell membrane mediates the effect; ＊ Insulin receptor is consisted by 2α subunits, which constitutes the recognition site, and 2β subunits, which contains a tyrosine kinase

The mechanism of insulin

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesisplasma membraneglycogenglycolysisfatty acid

Clinical use Diabetes mellitus 1 The only effective drug for type 1 diabetes Insulin must be injected or inhaled 2 The following situations of type 2 diabetes

2 The following situations of type 2 diabetes Not effectively controlled by food limitation & oral antidiabetic drugs;

Accompanies DKA & nonketotic hyperosmolar hyperglycemia coma; 2 The following situations of type 2 diabetes

2 The following situations of type 2 diabetes Accompanies serious infection, hyperpyrexia, injury, gestation and consumptive diseases.

Clinical use 3.Mild or moderate Diabetes companied with high fever,infection,hyperthyroidism, wasting disease,or operation, pregnancy.

4.Ketoacidosis and diabetes coma with high hyperosmolality

5. Others ＊ Hyperkalemia ＊ A component of GIK solution which is for limiting myocardial infarction & arrhythmias

(GIK) solution which contains 20 units of insulin, 3g of KCl 300 ml of 25% glucose solution

Adverse reactions 1.Insulin allergy: itching, redness, swelling, anaphylaxis shock

Because sensitivity is often to noninsulin protein contaminants The new highly purified insulin have markedly reduced the incidence of insulin allergy, especially local reactions

Glucocorticoid or H1 receptor blocker

2.Insulin resistance Acute resistance :infection,trauma,anti- insulin factor increase-corticosteroids. Treatment: remove different causes, increase dosage of insulin.

2.Insulin resistance Chronic resistance: antibody of insulin production, antibody of insulin production, number of insulin decrease, number of insulin decrease, receptor and affinity decrease. receptor and affinity decrease.

Treatment of chronic resistance Select insulin with less antigenicity. Try to avoid using insulin intermittently. Avoid hyperinsulinism and blood glucose fluctuation.

3.Hypoglycemia: nausea, hungry, tachycardia, sweating, and tremulousness. ＊ First aids needed while convulsions & coma happens

Fruit juice, soluble carbohydrates in severe hypoglycemia, i.v ml of 50% glucose solution or 1 mg of glucagon injected either sc or i.m. Treatment:

4. Local reaction - Lipodystrophy at injection sites: atrophy, localized infections at the site of injection.

Preventive action Sites of injection should be rotated and by use of an i.m rather than a s.c route of administration.

Section 2 Oral Antidiabetic Drugs ● Classification Meglitinides Thiazolidinediones α-glucosidase inhibitors Sulfonylureas Biguanides

І. Sulfonylureas Representative Drugs Representative Drugs 1st generation: 1st generation: tolbutamide chlorpropamide tolbutamide chlorpropamide 2nd generation: glybenclamide glyburide glybenclamide glyburide 3rd generation: 3rd generation: glimepiride glimepiride

The mechanism of SULFOUNYLUREAS

Hypoglycemic mechanism Hypoglycemic mechanism 1. Rapid mechanism: stimulation of insulin secretion Sulfonylurea receptor in β-cell membrane activated ATP-sensitive K + -channel inhibited Cellular membrane depolarized Ca 2+ entry via voltage-dependent Ca 2+ channel Insulin release

1. Hypoglycemic effect  Direct stimulation of insulin release from the β cells.  Reduced glucagon secretion.

1. Hypoglycemic effect  Improve tissue sensitivity to insulin. a.Direct: Increased receptor binding, improved postbinding action a.Direct: Increased receptor binding, improved postbinding action

1. Hypoglycemic effect  Improve tissue sensitivity to insulin. b.Indirect: Reduced hyperglycemia; decreased plasma free fatty acid concentration; b.Indirect: Reduced hyperglycemia; decreased plasma free fatty acid concentration; reduced hepatic insulin extraction reduced hepatic insulin extraction

2.Antidiuretic action Promote antidiuretic hormone(ADH) secretion, Promote antidiuretic hormone(ADH) secretion, Enhance ADH action. Enhance ADH action. Chlorpropamide Chlorpropamide

Decrease platelet adhesion, Promote plasminogen synthesis, Decrease sensitivity of capillary to vasoactive amine Gliclazide Gliclazide 3.Anticoagulation action

Clinical use Clinical use 1. Type 2 diabetes mellitus 1. Type 2 diabetes mellitus 2. Diabetes insipidus: chlorpropamide 2. Diabetes insipidus: chlorpropamide

Adverse reactions 1. Gastrointestinal disorders 1. Gastrointestinal disorders 2. Allergy 2. Allergy

3. Hypoglycemia 3. Hypoglycemia Chlorpropamide forbidden for aged & patients with functional disorder in liver or kidney. Chlorpropamide forbidden for aged & patients with functional disorder in liver or kidney. 4. Granulocytopenia, cholestasis & hepatic injury 4. Granulocytopenia, cholestasis & hepatic injury

Meglitinides Representative Drugs Representative Drugs Repaglinide Key point Key point ● To increase insulin release by inhibiting ● To increase insulin release by inhibiting ATP-sensitive K + -channel

● Unlike insulin release ● Unlike sulfonylureas, they have no direct effect on insulin release ● Used alone or together with to treat type 2 diabetes ● Used alone or together with biguanides to treat type 2 diabetes

● Carefully used for patients with kidney or liver impaired. ● Carefully used for patients with kidney or liver impaired.

Ⅱ. Ⅱ. Thiazolidinediones (Tzds) Representative Drugs Representative Drugs rosiglitazone troglitazone pioglitazone ciglitazone

Pharmacological effects ●Improving function of pancreas cells ●Improving function of pancreas β cells ●Ameliorating insulin resistance ●Ameliorating insulin resistance

Pharmacological effects ●Ameliorating fat metabolic disorder ●Preventing and treating type 2 diabetes mellitus and their cardiovascular complications ●Preventing and treating type 2 diabetes mellitus and their cardiovascular complications

Mechanism (possible) Mechanism (possible) Peroxisome proliferator- activated receptor-γ (PPAR-γ) activated Nuclear genes involved in glucose & lipid metabolism, adipocyte and other tissue differentiation activated

Clinical use Insulin resistance & type 2 diabetes mellitus Insulin resistance & type 2 diabetes mellitus

Adverse reactions occasionally induces hepatic injury Troglitazone occasionally induces hepatic injury

Ⅲ. Biguanides Representative Drugs Representative Drugs phenformin metformin

Key points ● insulin secretion unchanged, and appetite unchanged ● insulin secretion unchanged, and appetite unchanged ●Hypoglycemic mechanism remains unclear ●Hypoglycemic mechanism remains unclear

Their blood glucose-lowering action does not depend on the presence of functioning pancreatic β cells. Their blood glucose-lowering action does not depend on the presence of functioning pancreatic β cells. Currently proposed mechanisms of action : A.Mechanisms of Effects

1.Direct stimulation in peripheral tissue, Increase anaerobic glycolysis in the muscle, have no effects on aerobic oxidation. which increased glucose removal from blood. 2.Reduced hepatic and renal gluconeogenesis. A.Mechanisms of Effects

3.Slowing of glucose absorption from the GI tract. 4.Reduction of plasma glucagon levels. 5.Increased insulin binding to insulin receptors. A. A.Mechanisms of Effects

1.Mild Type Ⅱ diabetes(NIDDM) with refractory obesity. metformin B. Clinical uses

2.Combine with insulin or sulfonylureas in NIDDM or IDDM. B. Clinical uses

Contraindicated: Malfunction of liver and kidney, chronic heart or pulmonary failure, severe anemia, Positive urine ketone body

● Metformin also used to treat atherosclerosis for down-regulation of LDL& VLDL ● Metformin also used to treat atherosclerosis for down-regulation of LDL& VLDL ● Ketonemia & lactic acidosis are major adverse reactions ● Ketonemia & lactic acidosis are major adverse reactions

Ⅳ. α-glucosidase inhibitors Representative Drugs Representative Drugs acarbose voglibose miglitol

α – GLUCOSIDASE INHIBITOR

Key points ● To inhibit digestion of starch & disaccharides via competitively inhibiting intestinal ● To inhibit digestion of starch & disaccharides via competitively inhibiting intestinal α-glucosidase (sucrase, maltase, glycoamylase, dextranase)

Clinical uses Used alone or together with to treat type 2 diabetes Used alone or together with sulfonylureas to treat type 2 diabetes

● Main adverse reaction: flatulence, diarrhea, bellyache. ● Patients with inflammatory bowel disease & kidney impaired forbidden.

Ⅴ. Insulin secretagogues agent Insulin secretagogues agent Representative Drugs Representative Drugs Repaglinide

Key point ● To increase insulin release by inhibiting ● To increase insulin release by inhibiting ATP-sensitive K + -channel ● Unlike insulin release ● Unlike sulfonylureas, they have no direct effect on insulin release

Key point ● Used alone or together with to treat type 2 diabetes ● Used alone or together with biguanides to treat type 2 diabetes ● Carefully used for patients with kidney or liver impaired. ● Carefully used for patients with kidney or liver impaired.

HYPOGLYCEMIC DRUGS INSULIN Regular insulin Semilante insulin Lante insulin Rotamine zinc insulin Protamine zinc insulin ORAL HYPOGLYCEMIC DRUGS Sulfonylureas Biguanldes - Glucosidase inhibitor Thiazolidinedione SUMMARY

Sites of Action of Antidiabetic Agents

Treatment Avoiding tobacco use Avoiding tobacco use Correction of associated hypertension (<130/80 mmHg) Correction of associated hypertension (<130/80 mmHg) Improvement of glycemic control Improvement of glycemic control Consultation with an ophthalmologist Consultation with an ophthalmologist

Which one of the following statements is correct? A. sulfonylureas decrease the secretion of insulin. A. sulfonylureas decrease the secretion of insulin. B. tolbutamide is effective in Type 1 diabetics. B. tolbutamide is effective in Type 1 diabetics. C. sulfonylrueas increase both the release of insulin and the insulin-sensitivity of target tissue. C. sulfonylrueas increase both the release of insulin and the insulin-sensitivity of target tissue. D. glipizide increases glucagon secretion. D. glipizide increases glucagon secretion. E. chlorpropamide blocks insulin receptors. E. chlorpropamide blocks insulin receptors.

All of the following are correct EXCEPT: A.one of the most common side effects of oral hypoglycemic agents is gastrointestinal disturbance. B. the most serious consequence of insulin overdose is hypoglycemia. C.weight reduction is often of therapeutic help in obese Type II diabetics. D. sulfonylureas are contraindicated in patients with hepatic insufficiency. E. insulin and glucagon have similar effects on metabolism.

Diabetes patients with severe infection, appropriate USES large doses of insulin reason is: A. increase blood insulin resistance material A. increase blood insulin resistance material B. blood glucose intake use a large number of free fat in the hamper B. blood glucose intake use a large number of free fat in the hamper C. resistance to insulin receptor antibodies C. resistance to insulin receptor antibodies D. reduced numbers of insulin receptor D. reduced numbers of insulin receptor E. glucose transporter on the target cell membrane system disorder E. glucose transporter on the target cell membrane system disorder

Mechanism of metformin drugs for the treatment of diabetes is A. enhancing the role of insulin A. enhancing the role of insulin B. promote tissue glucose uptake B. promote tissue glucose uptake C. to stimulate endogenous insulin secretion C. to stimulate endogenous insulin secretion D. blockade of ATP sensitive potassium channels D. blockade of ATP sensitive potassium channels E. increase in the number of insulin receptors on target cell membranes E. increase in the number of insulin receptors on target cell membranes

Aged diabetes patients should not be used: A. gliclazide A. gliclazide B. chlorpropamide B. chlorpropamide C. tolbutamide C. tolbutamide D. metformin D. metformin E. phenformin E. phenformin