Diabetes Mellitus

• Autoimmune destruction of pancreatic β cells by glutamic acid decarboxylase (GAD) antibodies leading to insulin deficiency
• Typically presents in children (4-6 & 10-14) or adults < 25 years of age
• Genetic predisposition
  • HLA-linked (HLA-DQ, HLA-DR3, and HLA-DR4)
• Associated with other autoimmune conditions
  • Hashimoto thyroiditis
  • Type A gastritis
  • Celiac disease
  • Primary adrenal insufficiency
• Autoantibodies (not always detectable):
  • GAD autoantibodies:
    • Target insulin-producing pancreatic β cells
    • Autoimmune destruction of 80%–90% of cells
    • Leads to insulin deficiency and hyperglycemia.
• Pathophysiology:
  • Genetic susceptibility and environmental triggers; (often associated with previous viral infection) → autoimmune response with production of autoantibodies, e.g., anti-glutamic acid decarboxylase antibody (anti-GAD), anti-islet cell cytoplasmic antibody (anti-ICA) → progressive destruction of β cells in the pancreatic islets → absolute insulin deficiency → decreased glucose uptake in the tissues

• Caused by insulin resistance → يكون الجسم مقاوم لعمل الأنسولين
• Relative insulin deficiency → يوجد انسلوين لكن بكمية غير كافية
• Strong family history/genetic component
  • A child with one diabetic parent has a ∼ 40% lifetime risk of developing T2DM.
  • The concordance between monozygotic twins is significant, with some studies finding rates of > 75%.
• Adult onset typically > 40 years (Insulin production decreases with age)
• Gender: ♂ > ♀
• Risk factors
  • Positive family history
  • Physical inactivity
  • History of cardiovascular disease
  • Conditions associated with insulin resistance : e.g., severe obesity and high-calorie diet
  • Hypertension  
  • Dyslipidemia  
  • History of gestational diabetes
• Pathophysiology
  • Peripheral insulin resistance
    • Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
  • Pancreatic β cell dysfunction:

Type 1

1. DKA
   Type 1 DM often presents urgently with DKA :
   
   • Usually precipitated by a “tipping” event (e.g., viral illness, trauma, emotional stress)
   • Depressed mental status
   • Abdominal pain
   • Vomiting
   • Fruity “acetone” breath
2. Hyperglycemia:
   Type 1 DM can also present with classic symptoms of hyperglycemia:
   
   • Polydipsia
   • Polyphagia
   • Polyuria (can present as enuresis and nocturia in children)
   • Weight loss
   • Blurred vision

Type 2

Type 2 DM has a gradual onset, initially remaining asymptomatic for several years:

1. High glucose levels often detected on screening tests before symptoms appear
2. Can present with classic symptoms of hyperglycemia, as in type 1 DM
3. Sometimes diagnosed with hyperosmolar hyperglycemic state or signs of long-term complications before the diagnosis is known
4. Rarely, DKA present
5. Nonspecific symptoms due to hyperglycemia:
   • Fatigue
   • Malaise
   • Anorexia
   • Amenorrhea
   • Erectile dysfunction
   • Headache
   • Blurred vision
   • Dehydration
6. Skin manifestations:
   • Recurrent cellulitis or fungal infections
   • Poor or delayed wound healing
   • Generalized pruritus
   • Acanthosis nigricans: hyperpigmented velvet-like plaques on the skin of the axilla or neck or between the digits

Diagnosis of DM can be achieved using any of the 2 following criteria:

1. Random glucose ≥ 200 mg/dL along with classic symptoms (polyuria, polydipsia, and polyphagia)
   يعني لازم يكون مع المريض أعراض السكري بالإضافة لنتيجة الفحص
2. OR ≥ 2 abnormal test results for hyperglycemia in asymptomatic individuals
   فحصين أو أكثر من الفحوصات التالية يجب أن تكون غير طبيعية

الملخص: إما أن يكون المريض لديه أعراض السكري ويكون فحص الــ RBS أكثر من 200 أو أن يكون لديه نتيجة فحصين مرتفعين من الفحوصات الموجودة في الجدول

ملاحظة: يمكن أيضاً إجراء بعض الفحوصات الأخرى والتي تساعد على معرفة أي نوع من أنواع السكري يوجد لدى المريض
مثل

C-peptide, Antibody testing

No definitive cure exists for diabetes. Management centers around correcting high blood glucose with insulin (type 1) or oral medication (type 2), avoiding low blood glucose , and treating the clinical effects of chronic hyperglycemia.

Multidisciplinary approach

Initial management is with patient education and support.

• Lifestyle modifications (Balanced diet, Regular exercise, Weight loss with reduced caloric intake if overweight or obese)
• Smoking cessation to decrease the risk of comorbid complications
• Stress management
• Pharmacologic therapies to meet individualized glycemic goals:
  • Choice of medication depends on the level of HbA1c at the time of diagnosis
  • Need to be adjusted with CKD or intolerance

Oral medications

Classes of oral medications used to treat insulin -resistant diabetes (usually type 2):

• Biguanide ( metformin ): 1st-line drug of choice
• Sodium – glucose cotransporter-2 (SGLT-2) inhibitors: demonstrated benefit for cardiorenal outcomes, especially for heart failure hospitalization , risk of kidney disease progression, and mortality
• Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Sulfonylureas
• Thiazolidinediones

Insulin therapy

Insulin therapy is used to treat type 1 DM and sometimes type 2 DM when oral medications alone are no longer sufficient.

• Rapid-acting insulins: start working in 10–15 minutes
  • Glulisine 
  • Lispro 
  • Aspart
• Short-acting insulin :
  • Starts working in 30 minutes, peaks at 2–3 hours
  • Rapid-acting and short-acting insulins are used in combination with longer-acting insulins or in insulin pumps for type 1 diabetes
• Long-acting insulin : last 12–24 hours
  • NPH
  • Glargine
  • Detemir

Noninsulin injectable therapies

• Glucagon-like peptide-1 (GLP-1) receptor agonists: preferred in patients who already have cardiac or renal comorbidities :
  • Exenatide
  • Dulaglutide
  • Liraglutide 
  • Semaglutide  — also available in tablet form (Rybelsus)
• Amylin mimetic pramlintide (not often used):
  • Suppresses plasma glucagon secretion
  • Slows gastric emptying
  • Promotes satiety

Special considerations with insulin use

The dawn phenomenon:

• Early in the morning, the effect of exogenous insulin injected the day before disappears.
• Insulin-antagonistic hormones increase physiologically in the morning.
• May cause morning hyperglycemia

The Somogyi effect:

• Rebound morning hyperglycemia
• Response to hypoglycemia during the night after excessive amounts of exogenous insulin the evening before