Diabetes mellitus
is a clinical syndrome characterized by persistently high blood glucose values due to deficiency or diminished effectiveness of insulin.
OR
As per the WHO, diabetes mellitus (DM) is defined as a heterogeneous metabolic disorder characterised by common feature of chronic hyperglycaemia with disturbance of carbohydrate,fat and protein metabolism.
Diabetes is a group of metabolic disorder characterized by chronic hyperglycaemia associated with disturbances of carbohydrate, fat and protein metabolism due to absolute or relative deficiency in insulin secretion and/or action.
Diabetes causes long term damage, dysfunction and failure of various organs
Diagnostic Criteria
Main clinical features of diabetes are
Ø polyphagia(excesive hunger or increased appetite)
Ø polydipsia (abnormally great thirst as a symptom of disease)
Ø polyuria (abnormally large volumes of dilute urine)
Ø tiredness
Ø loss of weight
Ø blurring of vision
Classification and etiology
The main risk factors for DM are;
ü Genetic factors and
ü Environmental factor such as obesity , dyslipidemia, smoking, unhealthy diet, low physical activity, viral infection, drugs, age, HT.
Diabetes mellitus can be classified as follows:
1. Type 1 Diabetes Mellitus (T1DM) – due to autoimmune β-cell destruction
2. Type 2 Diabetes Mellitus (T2DM) – due to a progressive loss of β-cell insulin secretion frequently with underlying insulin resistance
3. Gestational Diabetes Mellitus (GDM) – diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation
4. Specific types of diabetes – due to other causes e.g., monogenic, diseases of the exocrine pancreas and drugs or chemicals.
TYPE I DM
It constitutes about 10% cases of DM. It was previously termed as juvenile-onset diabetes (JOD) due to its occurrence in younger age, and was called insulin-dependent DM (IDDM) because it was known that these patients have absolute requirement for insulin replacement as treatment.
However, in the new classification, neither age nor insulin-dependence are considered as absolute criteria.Instead is based on underlying etiology.
type I DM is further divided into 2 subtypes:
Subtype 1A (immune-mediated) DM
characterised by autoimmune destruction of β-cells which usually leads to insulin deficiency.
Subtype 1B (idiopathic) DM
characterised by insulin deficiency with tendency to develop ketosis but these patients
are negative for autoimmune markers.
Though type 1 DM occurs commonly in patients under 30 years of age, autoimmune destruction of β-cells can occurat any age.
TYPE 2 DM
This type comprises about 80% cases of DM. It was previously called maturity-onset diabetes, or non-insulin dependent diabetes mellitus (NIDDM) of obese and non obese type.
Although type 2 DM predominantly affects older individuals, it is now known that it also occurs in obese adolescent children Moreover, many type 2 DM patients also require insulin therapy to control hyperglycaemia or to prevent ketosis and thus are not truly non-insulin dependent contrary to its former nomenclature.
GESTATIONAL DM
About 4% pregnant women develop DM due to metabolic changes during pregnancy. Although they revert back to normal glycaemia after delivery, these women are prone to develop DM later in their life.
Uncontrolled gestational diabetes can lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia.
pathogenesis
Depending upon etiology of DM, hyperglycaemia may result from the following:
u Reduced insulin secretion
u Decreased glucose use by the body
u Increased glucose production.
WHO diagnostic Criteria 2006
ü Fasting plasma glucose level ≥ 7.0 mmol/L (126 mg/dL)
ü Plasma glucose≥ 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load in a glucose tolerance test.
ü Symptoms of hypogycaemia and casual plasma glucose ≥11.1 mmol/L (200 mg/dL)
ü Diagnosis of gestational diabetes (WHO criteria 2013)
ü Fasting plasma glucose 5.1–6.9 mmol/l
ü 2–hour plasma glucose 8.5–11.0 mmol/l following a 75g oral glucose load.
Complications of diabetes
Acute
Ø Diabetic ketoacidosis
Ø Hyperosmolar non-ketotic coma
Ø Hypoglycaemia
Chronic
Ø Microvascular (nephropathy, retinopathy,&peripheral nerves)
Ø Macrovascular (coronary artery disease, stroke&peripheray artery vessel)
Non-pharmacological management
ü Dietary control.
ü No smoking.
ü Avoid or limit alcohol intake .
ü Physical activity.
pharmacological management
treatment with oral hypoglycaemics
Targets for antidiabetics
1.Sulfonylureas
These agents are classified as insulin secretagogues, because
they promote insulin release from the β cells of the pancreas. The sulfonylureas in current use are the second-generation drugs glyburide, glipizide, and glimepiride.
Mechanism of action
The main mechanism of action includes stimulation of insulin release from the β cells of the pancreas. Sulfonylureas block ATP-sensitive K+ channels, resulting in depolarization, Ca2+ influx, and insulin exocytosis. In addition, sulfonylureas may reduce hepatic glucose production and increase peripheral insulin sensitivity
Adverse effects
Major adverse effects of the sulfonylureas are weight gain, hyperinsulinemia, and hypoglycemia.
2. Biguanides
Metformin , the only biguanide, is classified as an insulin sensitizer. It increases glucose uptake and use by target tissues, thereby decreasing insulin resistance. Unlike sulfonylureas, metformin does not promote insulin secretion. Therefore, hyperinsulinemia is not a problem, and the risk of hypoglycemia is far less than that with sulfonylureas.
Mechanism of action
The main mechanism of action of metformin is reduction of hepatic gluconeogenesis. Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization. Weight loss may occur because metformin causes loss of appetite. Metformin may be used alone or in combination with other oral agents or insulin. Hypoglycemia may occur when metformin
is taken in combination with insulin or insulin secretagogues, so adjustment in dosage may be required.
If the maximum dose of metformin does not result in adequate glycaemic control,
sulphonylureas
such as glimepiride (Amaryl), glipizide (Glucotrol, Metaglip), and glyburide (DiaBeta, Micronase) may be added, starting with the lower dose and increasing until control is achieved or the maximum dose is reached.
If a combination of both medicines is still inadequate, then insulin should be added.
3. Glinides
This class of agents includes repaglinide and nateglinide . Glinides are also considered insulin secretagogues.
Mechanism of action
Like the sulfonylureas, the glinides stimulate insulin secretion. They bind to a distinct site on the β cell, closing ATP-sensitive K+ channels, and initiating a series of reactions that results in the release of insulin.
In contrast to the sulfonylureas, the glinides have a rapid onset and a short duration of action. They are particularly effective in the early release of insulin that occurs after a meal and are categorized as postprandial glucose regulators. Glinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action. This would increase the risk of serious hypoglycemia.
Glinides should be taken prior to a meal and are well absorbed after oral administration.
4. Thiazolidinediones
The thiazolidinediones are also insulin sensitizers. The two members of this class are pioglitazone and rosiglitazone. Although insulin is required for their action, the thiazolidinediones do not promote its release from the β cells, so hyperinsulinemia is not a risk.
Mechanism of action
The thiazolidinediones lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ(PPARγ), a nuclear hormone receptor.
Activation of PPARγ regulates the transcription of several insulin responsive genes, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscles.
Effects of these drugs on cholesterol levels are of interest.Rosiglitazone increases LDL cholesterol and triglycerides, whereas pioglitazone decreases triglycerides. Both drugs increase HDL cholesterol. The TZDs can be used as monotherapy or in combination with other glucose-lowering agents or insulin.
5. α-Glucosidase inhibitors
Acarbose and miglitol are oral agents used for the treatment of type 2 diabetes.
Mechanism of action
Located in the intestinal brush border, α-glucosidase enzymes break down carbohydrates into glucose and other simple sugars that can be absorbed. Acarbose and miglitol reversibly inhibit α-glucosidase enzymes
6. Sodium–glucose cotransporter 2 inhibitors
Canagliflozin and dapagliflozin are the agents in this category of drugs for type 2 diabetes.
Mechanism of action
The sodium–glucose cotransporter 2 (SGLT2) is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney. By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose.
Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic diuresis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure. However, they are not indicated for the treatment of hypertension
7. Dipeptidyl peptidase-4 inhibitors
Alogliptin , linagliptin , saxagliptin and sitagliptin are orally active dipeptidyl peptidase-4 (DPP-4) inhibitors used for the treatment of type 2 diabetes.
Mechanism of action
These drugs inhibit the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1. Prolonging the activity of incretin hormones increases insulin release in response to meals and reduces inappropriate secretion of glucagon.
DPP-4 inhibitors may be used as monotherapy or in combination with sulfonylureas, metformin, TZDs, or insulin.
Treatment with Insulin Injection in Type 2 Diabetes
Insulin injections are indicated in T2DM in the following conditions:
ü Initial presentation with fasting blood glucose more than 15 mmol/l.
ü Presentation in hyperglycaemic emergency.
ü Peri-operative period especially major or emergency surgery.
ü Other medical conditions requiring tight glycaemic control.
ü Organ failure, Renal, liver, heart etc.
ü Diabetes not well controlled with diet or oral drugs.
ü Latent autoimmune diabetes of adults (LADA).
ü Contraindications to oral drug.
MECHANISM OF ACTION OF INSULIN
Types of Insulin preparations
Ultra Short-acting
| Intermediate Acting
| Long Acting
|
Regular (crystalline) insulin | Neural protamine Hagedorn (NPH) (Aka. Isophane insulin)
| Ultralente (insulin zinc-crystalline)
|
Insulin Lispro
| Lente (Insulin Zinc)
| Insulin glargine
|
Insulin Aspart |
| Insulin determir
|
Insulin Glulisine |
| Tresiba - new
|
Inhalable Insulin (Exubera, Afreza)
|
|
|
Adverse reactions to insulin
Hypoglycemia is the most serious and common adverse reaction to
insulin .
Other adverse reactions include weight gain, local injection site reactions, and lipodystrophy. Lipodystrophy can be minimized by rotation of injection sites. Diabetics with renal insufficiency may require a decrease in insulin dose.
ü Left untreated, retinopathy, nephropathy, neuropathy, and cardiovascular complications may result.
References
Ø harsh-mohan-textbook-of-pathology-6th-ed
Ø Standard treatment guidelines and national essential medicines list (STG & NEMLIT 2021 )
Ø https://www.webmd.com/diabetes/type-2-diabetes
Ø LippincottIllustrated Reviews: Pharmacology Sixth Edition
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