Diabetes Types, Causes and Management

Diabetes is a metabolic disease which is chronic and is characterized by hyperglycemia caused when the pancreas secret inadequate insulin (a blood sugar regulatory hormone) or the body’s cells do not respond properly to insulin, or both. The disease is known by different names. Diabetes in Greek word means “Siphon” because the patient pass water too much like a siphon.

Later the disease was named “Diabainein” by Aretus Cappadocian, a Greek physician. The name “diabetes” itself comes from the English adoption of Medieval Latin diabetes. In China, the disease is termed as “Sweet Urine Disease” because the patient’s urine attracts ants.

The disease is common in both genders (male and female). The symptom includes- polyuria, polydipsia, weight loss, and in some instances, polyphagia and blurred vision. The disease may accompany the impairment of growth and susceptible to certain infections.

Long term Health implications of Diabetes.

Retinopathy

It is a potential loss of vision that occurs due to accumulated damage to the small blood vessels in the retina. Such visual impairment generally observed in the patient with over 15 years of the disease;

Nephropathy

the failure in the renal system, the leading cause of diabetes;

Neuropathy

It is damage to the nerves with the symptoms of tingling, pain, numbness, or weakness in the feet and hands; peripheral neuropathy with reduced blood flow increases the risk of foot ulcers that eventually lead to limb amputation, and Charcot’s joints; autonomic neuropathy causing genitourinary, gastrointestinal, cardiovascular disease and sexual relationship dysfunction, and cerebrovascular, hypertension, and abnormalities of lipoprotein metabolism are some other diabetes associates ailments.

Types of diabetes and their causes

The vast majority of diabetes cases fall in two main etiopathogenetic categories: Type 1 and Type 2 diabetes.

Type 1 diabetes

The disease is also known as insulin-dependent diabetes, juvenile diabetes, or early-onset diabetes because it often develops early in teenage years or a person’s adulthood before 40 years of age. It constitutes nearly 10% of all diabetes cases.Type 1 diabetes has a variable rate of pancreatic β cell destruction. It is rapid in infants and children while slows down in adults.

Ketoacidosis may be evidenced in children and adolescents as the first manifestation of the disease. Other individuals may have mild fasting hyperglycemia that can rapidly progress to severe hyperglycemia and ketoacidosis due to stress or infections.

Adults may retain residual β cell function and prevent ketoacidosis for years, but there is little or no secretion of insulin at the later stages of the disease due to undetectable levels of plasma C-peptide and requires insulin for survival and are at risk of ketoacidosis.

 

>>Fast track>> Plasma C-peptide: Proinsulin C-peptide is a 31 amino acid long peptide important for the biosynthesis of insulin. It connects the A and B chain of the insulin and facilitates the assembly, folding, and processing of insulin in the endoplasmic reticulum.

 

Patients of type 1 diabetes are susceptible to other autoimmune disorders such as Addison’s disease, Graves’ disease, Hashimoto’s thyroiditis, vitiligo, celiac sprue, myasthenia gravis, pernicious anemia, and autoimmune hepatitis.

Causes of Type 1 diabetes

Type 1 diabetes results from a cellular mediated autoimmune destruction of the pancreatic β cell. Markers that involves in immune destruction of β cell include- islet cell antibodies, autoantibodies to tyrosine phosphate IA-2 and IA-2β, and autoantibodies to glutamic acid decarboxylase (GAD65).

These autoantibodies are witnessed in 85-90% of diabetic individuals when fasting hyperglycemia is initially detected. This immune-mediated diabetes has a strong HLA (Human Leukocyte Antigen) association, with linkage to the DQA and DQB genes, and this is influenced by DRB genes. These alleles HLA-DR/DQ can either be predisposing or preventive.

>>Fast track>> Human Leukocyte Antigen complex is the human version of the major histocompatibility complex (MHC).  DQA, DQB, and DRB are genes of this complex. The function protein complex DQαβ heterodimer, formed by the DQA and DQB, exhibits foreign peptides to the immune system to trigger the immune response of the body.

Idiopathic diabetes

This is a form of type 1 diabetes with no known etiologies. It is strongly inherited, witness lack of β cell autoimmunity, and has no association with HLA. Such a diabetic patient suffers from episodic ketoacidosis and evidence varying degrees of insulin deficiency between episodes.

Type 2 diabetes

This type of diabetes is known as insulin-independent diabetes or adult-onset diabetes. It encompasses individuals resistant to insulin and has relative insulin deficiency. Type 2 diabetes accounts for maximum (90-95% approx.) of all diabetic cases. There is no autoimmune destruction of β cells, and no specific etiologies are known.

Type 2 diabetes remains undiagnosed for years due to the gradual development of hyperglycemia. At an early stage, it is not severe enough for the patient to witness any of the symptoms of the onset of diabetes.

Patients may have maintained normal or elevated insulin level, but higher blood glucose level is expected too if their β cell function is normal. Hence, with the defective insulin secretion and inability to compensate insulin resistance, patients are at risk of developing microvascular and macrovascular complications.

Causes of Type 2 diabetes

With an increase in age, the risk of developing type 2 diabetes increases. Obesity, lack of physical activity are an important cause of this diabetes. Not limited to individuals with hypertension or dyslipidemia, it also occurs in women with prior gestational diabetes mellitus (GDM). The occurrence of the disease also varies with racial/ ethnic subgroups.

>>Fast track>> Gestational Diabetes Mellitus (GDM) is the occurrence of a variable degree of glucose intolerance with onset or first recognition during pregnancy. Obesity and other factors that contribute to insulin resistance manifest to enhance those women with GDM at the high risk of developing type 2 diabetes, usually after pregnancy.

Maturity-Onset Diabetes of the Young (MODY)

It is the onset of hyperglycemia in as early as before attaining the age of 25. MODY is associated with monogenetic defects of β cells and is characterized by impaired insulin secretion without any defect of insulin action.

Causes of MODY

It is hereditarily transmitted in an autosomal dominant pattern. It is caused by the genetic defect of β cell function.

Types of MODY	Cause of defection	Associated chromosome number
MODY 1	Mutation in hepatocyte nuclear factor (HNF)-4 α	Chromosome no. 20
MODY 2	Mutation in the glucokinase gene	Chromosome no. 7p
MODY 3	Mutation in hepatocyte nuclear factor (HNF)- 1α	Chromosome no. 12
MODY 4	Mutation in insulin promoting factor (IPF)- 1	Chromosome no. 13
MODY 6	Mutation in Neuro D1	Chromosome no. 2
MODY 7	Mutation in carboxyl ester lipase	Chromosome no. 9

 

Transient and permanent neonatal diabetes are such newborn child diseases where there is imprinting defect of ZAC/HYAMI gene on chromosome 6q24 and defect in KCNJ11 gene encoding Kir6.2 subunit of β cell KATP channel, respectively.

Point mutations in mitochondrial DNA (mtDNA) at position 3,243 in the tRNA leucine coding gene leads to transition A-to- G nucleotide are also associated with diabetes and deafness.

Other defects that cause diabetes

Genetic defects in insulin action

Genetically determined mutation in the cell’s insulin receptor causes metabolic abnormalities in the insulin action. This abnormality may lead to hyperinsulinemia, modest hyperglycemia, and severe diabetes.

Drug-induced diabetes

Certain drugs or chemicals are known to impair insulin secretion. Although rare, the toxin such as Vacor (a rat toxicant) and intravenous pentamidine destroys the pancreatic β cell permanently. Other chemicals and hormones, such as nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, β-adrenergic agonists, thiazides, γ- interferon, Dilantin, etc. impair the insulin action.

Diseases of the exocrine pancreas

Injury of the pancreas due to pancreatitis, pancreatectomy, pancreatic carcinoma, trauma, and certain infection can cause diabetes. Adenocarcinoma, cystic fibrosis, hemochromatosis also cause damage to the β cells and impair insulin secretion.

Endocrinopathies

Several diseases of endocrine glands such as hyperthyroidism, hypothyroidism antagonize insulin action.

Management

At the instance, diabetes is not a curable disease, but it can be treated and controlled through various means. The primary goals being-

Maintaining normal blood glucose levels by balancing food (nutritional therapy) with medication (drug therapy) and activity (exercise therapy) and maintaining blood cholesterol and triglyceride levels near the normal range. Retaining blood pressure below 140 (systolic) and 90 (diastolic), i.e., below 140/90 mm Hg.

Knowing about the disease is necessary to manage the disease. Certain medications, therapy in coordination with health care personnel, and awareness can control diabetes and living a healthy life. Additionally, self-monitoring of blood glucose level (SBMG), and making aware of the causes and complications of diabetes, motivating towards daily exercise for controlling weight gain, are needed to control the disease. Lack of all the above mentioned proper care and management of diabetes may lead a person to multi-organ failure and finally to death.

 Nutritional Therapy

Factor	Type 1 Diabetes Mellitus	Type 2 Diabetes Mellitus
Total calories	Increase in caloric intake possibly necessary to achieve desired body weight and restore body tissues	Reduction in caloric intake desirable for overweight or obese patient
Effect of diet	Diet and insulin necessary for glucose control	Diet alone possible for glucose control
Distribution of calories	Equal distribution of carbohydrate through meals or adjustment of carbohydrates for insulin activity	Equal distribution recommended; low-fat diet desirable consistency of carbohydrate at meals desirable.
Consistency in daily intake	Necessary of glucose control	Desirable for weight reduction and moderation of blood glucose level
Uniform timing of meals	Crucial for NPH insulin programs; flexibility with multidose rapid-acting insulin	Desirable but not essential, unless using insulin or sulfonylureas
Internal and bedtime snacks	Frequent necessary	Is best on patients eating habits and preferences; may be required if using insulin or sulfonylurea
Nutrition supplement for exercise programs	Carbohydrates 20 g/hr for moderate physical activities	May be necessary if the patient-controlled on sulfonylurea or insulin.

 

Exercise Therapy

Different amounts of calories are burned through exercise as a part of controlling weight gain.

Light activity (100-200 kcal/hr)

Moderate activity (200-350 kcal/ hr)

Vigorous activity (400- 900kcal/hr)

Drug Therapy

Insulin

Classification	Examples, Clarity of Solution
Rapid-acting insulin	Lipro (Humalog), clear( 15-30min onset; peak 30-90min) Aspart (NovoLog), clear(10-20 min; peak 40-50min) Glulisine (Apidra), clear (20-30 min; peak 40-90min)
Short-acting Insulin	Regular (Human R, Novolin R, ReliOn N), cloudy
Intermediates –acting insulin	Glargine (Lantus), clear Detemir (Levemir), clear
Combination therapy  (premixed)	NPH/regular 70/30, (Humulin 70/30, Novalin 70/30, ReliOn 70/30), cloudy NPH/regular 50/50* (Humulin 50/50), cloudy Lispro protamine/lispro 75/25* (Humalog Mix 75/25), cloudy Aspart protamine/ aspart 70/30 *(Novalog Mix 70/30), cloudy

Oral and other agents

Type	Route of Administration	Mechanism of Action	Side Effects
Sulfonylureas (Glipizide, Glyburide)	Oral dose range 5-20mg/day	release of insulin from pancreatic islets upon stimulation, decrease glycogenolysis and gluconeogenesis; enhance cellular sensitivity to insulin	Weight gain, hypoglycemia
Meglitinides (Repaglinide)	Oral	Stimulate a rapid and short-lived release of insulin from the pancreas	Weight gain, hypoglycemia
Biguanide (Metformin)	Oral (500- 3,000 mg/day)	Decrease rate of hepatic glucose production; which helps in glucose uptake by tissues, especially muscles	Diarrhea, lactic acidosis
α-Glucosidase inhibitors Acarbose	Oral 25-75 mg tid PC	Delay absorption of glucose from GI tract	Gas, abdominal pain, diarrhea.
Thiazolidinediones Pioglitazone (Actos)	Oral 15-45 mg/day	Increment of glucose  uptake in muscle; decrease endogenous glucose production	Weight gain edema not  recommended for  patients with heart failure
Dipeptidyl Peptidase-4 inhibitors Sitagliptin (Januvia)	Oral	Enhances the Incretin system, stimulates the release of insulin from pancreatic β cells, and    decreases hepatic glucose production	Upper respiratory tract infection, sore throat, headache, diarrhea
Combination Therapy Gleucovanc	Oral	Combination of metformin and glyburide	Nausea, diarrhea, abdominal pain, lactic acidosis, weight gain hypoglycemia
Incretin Mimetic Exenatide (Byetta)	Subcutaneous	Decreases: stimulates the release of  insulin; glucagon secretion; Gastric emptying; Increases: satiety	Nausea, vomiting, hypoglycemia, diarrhea, headache
Amylin Analog Pramlintide (Symlin)	Subcutaneous; only in abdomen or thigh	Decreases: Gastric emptying;  glucagon secretion;     endogenous glucose output from the liver; Increases: satiety	Hypoglycemia, nausea, vomiting, decreased appetite, headache.

 

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Insulin Glucose Metabolism

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