Diabetes and Its Complications

Definition

Diabetes is a multisystemic metabolic abnormality affecting metabolism of glucose, fat, protein, fluid, and electrolytes arising from absolute or relative deficiency of insulin of which chronic hyperglycemia is the sin qua non.

Diabetes is a significant and growing threat to global health. Worldwide, diabetes affects 417 million people in 2017, the world prevalence is predicted to reach 620 million by 2040. The developing countries are more likely to be affected.

Type 2 constitutes ≈ 70-90% and type 1 ≈ 1-10% diabetes among Northern Europe.

The presence of typical features of the disease:

• polyphagia,
• polydipsia,
• polyuria,
• and weight loss with either:

• FBS ≥ 126mg/dl (7.0mmol/L), or
• RBS ≥ 200mg/dl (11.1mmol/L), or
• HbA1c ≥ 6.5% (48mmol/mol).

Absence of symptoms, RBS ≥ 200mg/dl (11.1mmol/L). You have to do

• FBS or
• HbA1c,

and if above the aforementioned.

Absence of symptoms but

• FBS = 100mg/dL - 125mg/dL (5.6 to 6.9mmol/l)
• RBS = 140-199mg/dL (7.8-11mmol/L)
• HbA1c = 5.7-6.4% (38-47mmol/mol)

= Intermediate glycemia will go for OGTT. If found to be as 1, then diagnosed.

1. Type 1 diabetes (immune-mediated beta cell destruction, usually leading to absolute insulin deficiency)
2. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance)
3. Specific types of diabetes
   1. Genetic defects of beta cell development or function characterized by mutations in:
      1. Hepatocyte nuclear transcription factor (HNF) 4α (MODY 1)
      2. Glucokinase (MODY 2)
      3. HNF-1α (MODY 3)
      4. Insulin promoter factor-1, HNF-1β, NeuroD1, and others leading to other forms of MODY
      5. Insulin, subunits of ATP-sensitive potassium channel leading to permanent neonatal diabetes
      6. Mitochondrial DNA
      7. Other pancreatic islet regulators/proteins such as KLF11, PAX4, BLK, GATA4, GATA6, SLC2A2 (GLUT2), RFX6, GLIS3
   2. Transient neonatal diabetes
   3. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipase
   4. Genetic defects in insulin action, including type A insulin resistance, Leprechaunism, Rabson-Mendenhall syndrome, Lipodystrophy syndromes
   5. Endocrinopathies—acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma
   6. Drug- or chemical-induced—glucocorticoids, vacor (a rodenticide), pentamidine, nicotinic acid, diazoxide, β-adrenergic agonists, thiazides, calcineurin and mTOR inhibitors, hydantoins, asparaginase, α-interferon, protease inhibitors, antipsychotics (atypicals and others), epinephrine
   7. Infections—congenital rubella, cytomegalovirus, coxsackievirus
   8. Uncommon forms of immune-mediated diabetes—“stiff-person” syndrome, anti-insulin receptor antibodies
   9. Other genetic syndromes sometimes associated with diabetes—Wolfram’s syndrome, Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome
4. Gestational diabetes mellitus (GDM)

• Family history of diabetes (i.e., parent or sibling with Type 2 Diabetes)
• Overweight or obese (BMI ≥ 25 kg/m², ≥ 23 kg/m² in Asian Americans, or other ethnically relevant definition for overweight)
• Physical inactivity
• Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
• Previously identified with IFG, IGT, or a hemoglobin A1c of 5.7–6.4%
• History of GDM (Gestational Diabetes Mellitus)
• Hypertension (blood pressure ≥ 140/90 mmHg)
• HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L)
• Polycystic ovary syndrome or acanthosis nigricans
• History of cardiovascular disease

	Features	Type 1	Type 2
1	Frequency	10%-20%	80%-90%
2	Age of onset	Early, <35 y	Late, >40 y
3	Type of onset	Abrupt and severe	Gradual and insidious
4	Weight	Normal	Obese or nonobese
5	HLA	Linked to HLA DR3, HLA DR4, HLA DQ	No HLA association
6	Family history	< 20%	Approximately 60%
7	Genetic locus	Unknown	Chromosome 6
8	Diabetes in identical twins	50% concordance	80% concordance
9	Pathogenesis	Autoimmune destruction of β cells	Insulin resistance impaired insulin secretion
10	Islets of cell antibodies	Yes	No
11	Blood insulin level	Decreased insulin	Normal or increased insulin
12	Islet-cell changes	Insulin cell depletion	No insulitis, later fibrosis
13	Amyloidosis	Infrequent	Common in chronic cases
14	Clinical management	Insulin, diet	Diet, exercise, oral drugs, insulin
15	Acute complications	Ketoacidosis	Hyperosmolar coma
HLA, human leukocyte antigen

• CBC-ESR, E, U, Cr, Ca, Phosp, ECG, Echo, FLP, LFT, Abd-pelvis Uss, Early morning urine sediment for microscopy, Urinalysis, FBS, RBS/2Hrpp, HbA1c
• Healthy diet/ Regular exercise
• Drugs
  • Insulin: short/fast acting, intermediate, premixed, long acting
  • Oral drugs:
    • Sulphonylureas
    • Biguanides
    • Alpha glucosidase inhibitors
    • Thiazolidinediones
    • Dipeptidyl peptidase-4 (DPP-4) inhibitors
    • Glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists)
    • Meglitinides
    • Sodium-glucose transporters
    • Others
      • Dopamine agonist
      • Amylinomimetic drug
• Blood pressure drugs, antiplatelets, cholesterol drugs

• Hypoglycemia
• Ketoacidosis
• Hyperglycemia hyperosmolar state
• Uremic acidosis
• Lactic acidosis

Differences between Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS)
	DKA	HHS
Glucose, mmol/L (mg/dL)	13.9–33.3 (250–600)	33.3–66. (600–1200)
Sodium, meq/L	125–135	135–145
Potassium	Normal to ↑	Normal
Creatinine	Slightly ↑	Moderately ↑
Osmolality (mosm/mL)	300–320	330–380
Plasma ketones	++++	+/-
Serum bicarbonate, meq/L	<15	Normal to slightly ↓
Arterial pH	6.8–7.3	>7.3
Arterial PCO, mmHg	20–30	Normal
Anion gap (Na – [Cl + HCO3])	↑	Normal to slightly ↑

A. Microvascular

1. Eye disease
   • Retinopathy (nonproliferative/proliferative)
   • Macular edema
2. Neuropathy
   • Sensory and motor (mono- and polyneuropathy)
   • Autonomic
3. Nephropathy (albuminuria and declining renal function)

B. Macrovascular

1. Coronary heart disease
2. Peripheral arterial disease
3. Cerebrovascular disease

Chronic Complications of Diabetes - Other

• Gastrointestinal (gastroparesis, diarrhea)
• Genitourinary (uropathy/sexual dysfunction)
• Dermatologic
• Infectious
• Cataracts
• Glaucoma
• Cheiroarthropathy (Thickened skin and reduced joint mobility)
• Periodontal disease
• Hearing loss
• Other comorbid conditions associated with diabetes (relationship to hyperglycemia is uncertain): depression, obstructive sleep apnea, fatty liver disease, hip fracture, osteoporosis (in type 1 diabetes), cognitive impairment or dementia, low testosterone in men.

Pathogenesis of Chronic Diabetes Mellitus Complications

• Glycation of proteins and macromolecules
• Overactivity of the polyol pathway
• Activation of protein kinase C
• Abnormal microvascular blood flow