DIABETES

DIABETICS

It is a metabolic disorder characterized by hyperglycemia due lack of pancreatic hormone, insulin.

Types of diabetes:

1. Diabetes mellitus: It is an endocrine disorder caused due to insulin deficiency and insulin resistance.

Symptoms: polyuria, thirst, fatigue, weight loss, blurred vision, pruritis.

            The subtypes of diabetes mellitus are

A. Type 1: Insulin dependent

B. Type 2: Non insulin dependent

C. Gestational diabetes

2. Diabetes insipidus: It is a rare metabolic disease caused due to the deficiency of the pituitary hormone vasopressin, which regulate the reabsorption of water in the kidneys.

A. Type 1 diabetes: Type 1 diabetes most commonly afflicts individuals in puberty or early adulthood, but some latent forms can occur later in life. The disease is characterized by an absolute deficiency of insulin caused by massive β-cell necrosis. Loss of β-cell function is usually ascribed to autoimmune-mediated processes directed against the β cell, and it may be triggered by an invasion of viruses or the action of chemical toxins. As a result of the destruction of these cells, the pancreas fails to respond to glucose.

 Symptoms of insulin deficiency: Polyuria, polydipsia, polyphagia, and weight loss. Type 1 diabetics require exogenous insulin to avoid the catabolic state that results from and is characterized by hyperglycemia and life-threatening ketoacidosis.

Cause of Type 1 diabetes: The development and progression of nephropathy, neuropathy, and retinopathy are directly related to the extent of glycemic control.

B. Type 2 diabetes: Most diabetics are Type 2. The disease is influenced by genetic factors, aging, obesity, and peripheral insulin resistance rather than by autoimmune processes or viruses. Causes: In Type 2 diabetes, the pancreas retains some β-cell function, but variable insulin secretion is insufficient to maintain glucose homeostasis. Type 2 diabetes is frequently accompanied by the lack of sensitivity of target organs to either endogenous or exogenous insulin. This resistance to insulin is considered to be a major cause of this type of diabetes.

Pathophysiology:

Insufficient insulin production

Reduced tissue uptake of glucose

Intracellular hypoglycemia                                                                 extra cellular hyperglycemia

Glucogenesis and gluconeogensis                      hyper osmotic plasma

                                                                           Hyperglycemic coma

                                                                            Blood glucose and renal threshold

 Osmotic diuresis , polyurea, polydipsia

Complications: Nephropathy, neuropathy, ketosis, diabetic retinopathy.

Diagnosis:

1. Urine analysis: glucosuria, nitroprusside test

2. Blood sugar testing: fasting glucose level, post prondial glucose level, random glucose level

3. Glycated hemoglobin levels

4. Triglyceride estimations

Drug therapy:

1. Insulin and Its Analogs: Insulin is a polypeptide hormone, consisting of a two peptide chains that are linked by a disulfide bonds. It is synthesized as a precursor (pro-insulin) that undergoes proteolytic cleavage to form insulin and C peptide, both of which are secreted by the islets cells of the pancreas.

Adverse reactions to insulin: Long-term diabetics often do not produce adequate amounts of the counter-regulatory hormones (glucagon, epinephrine, and growth hormone), which normally provide an effective defense against hypoglycemia. Other adverse reactions include allergic reactions, weight gain, lipodystrophy (less common with human insulin), and local injection site reactions. Diabetics with renal insufficiency may require adjustment of the insulin dose.

 Insulin Preparations and Treatment:

Long-acting insulin preparations:

Insulin glargine: The isoelectric point of insulin glargine is lower than that of human insulin, leading to precipitation at the injection site, thereby extending its action. It is slower in onset than NPH insulin and has a flat, prolonged hypoglycemic effect like the other insulin’s, it must be given subcutaneously.

Insulin detemir: Insulin detemir has a fatty-acid side chain. The addition of the fatty-acid side chain enhances association to albumin. Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine.

Intermediate-acting insulin: Neutral protamine Hagedorn (NPH) insulin is a suspension of crystalline zinc insulin combined at neutral pH with a positively charged polypeptide, protamine. It is also called as isophane. Its duration of action is intermediate. This is due to delayed absorption of the insulin because of its conjugation with protamine, forming a less-soluble complex. NPH insulin should only be given subcutaneously (never intravenously) and is useful in treating all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia. It is used for basal control and is usually given along with rapid- or short-acting insulin for mealtime control.

Short acting insulin preparations:

Regular insulin is short-acting, soluble, crystalline zinc insulin. Regular insulin is usually given subcutaneously (or intravenously in emergencies), and it rapidly lowers blood glucose.

1. Oral hypoglycaemic drugs:

1. Sulfonylurea’s: They promote insulin release from the I² cells of the pancreas. The primary drugs used today are tolbutamide and the second-generation derivatives, glyburide, glipizide, and glimepiride.

Mechanisms of action: These include

1) Stimulation of insulin release from the I² cells of the pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx

 2) Reduction in hepatic glucose production and

3) Increase in peripheral insulin sensitivity.

Pharmacokinetics: Given orally, these drugs bind to serum proteins, are metabolized by the liver, and are excreted by the liver or kidney.

Adverse effects: weight gain, hypoglycemia, hyperinsulinemia, renal impairment.

1. Biguanides: Metformin, the only available biguanide currently, it is classed as an insulin sensitizer; it increases glucose uptake and utilization by target tissues, thereby decreasing insulin resistance.

Mechanism of action: The main mechanism of action of metformin is reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis. Metformin may be used alone or in combination with one of the other agents, as well as with insulin. Hypoglycemia has occurred when metformin was taken in combination.

Pharmacokinetics: Metformin is well absorbed orally; it is not bounded to serum proteins, and is not metabolized. Excretion is via the urine.

Adverse effects: Gastrointestinal effects. Metformin is contraindicated in acute myocardial infarction, diabetics with renal and/or hepatic disease, severe infection, or diabetic ketoacidosis. Rarely, potentially fatal lactic acidosis has occurred. Long-term use may interfere with vitamin B12 absorption.

1. Meglitinide:  This class of agents includes and nateglinide

Mechanism of action: They bind to a distinct site on the sulfonylurea receptor of ATP-sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin.

Pharmacokinetics: These drugs are well absorbed orally after being taken 1 to 30 minutes before meals. Both meglitinides are metabolized to inactive products by CYP3A4  in the liver and are excreted through the bile.

Adverse effects: hypoglycemia, Weight gain is less of a problem with the meglitinides than with the sulfonylureas. These agents must be used with caution in patients with hepatic impairment.

1. Thiazolidinediones : Another group of agents that are insulin sensitizers are the thiazolidinediones (TZDs) or, more familiarly the glitazones. Troglitazone

Mechanism of action: The TZDs lower insulin resistance, they are known to target the peroxisome proliferatorâtion “activated receptor-I³”a nuclear hormone receptor. Hyperglycemia, hypertriacylglycerolemia, hyperinsulinemia, and elevated HbA1c levels are improved. Pharmacokinetics: Both pioglitazone and rosiglitazone are absorbed very well after oral administration and are extensiveely bound to serum albumin. Both undergo extensive metabolism by different cytochrome P450 isozymes the metabolites of rosiglitazone are primarily excreted in the urine. No dosage adjustment is required in renal impairment.

Adverse effects: hepatotoxicity, to increase subcutaneous fat or due to fluid retention, osteopenia and increased fracture risk. Other adverse effects include headache and anemia.

1. α Glucosidase inhibitors:

Mechanism of action: These drugs are taken at the beginning of meals. They act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels. This enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars.

Pharmacokinetics: Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.

Adverse effects: diarrhea, flatulence, and abdominal cramping.

Contraindication: Patients with colonic ulceration, inflammatory bowel disease, or intestinal obstruction should not use these drugs.

Diabetes, oral hypoglyceamics, insulin