Diabetes Mellitus: Types 1 & 2 Pathogenesis

Diabetes Mellitus (DM) Overview

• A group of metabolic diseases characterized by hyperglycemia.
• Hyperglycemia stems from defects in insulin secretion, insulin action, or both.
• Chronic hyperglycemia leads to long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Type 1 DM Pathogenesis

• It is the result of lymphocytic infiltration and destruction of insulin-secreting beta cells in the islets of Langerhans within the pancreas.
• As beta-cell mass declines, insulin secretion decreases.
• Adequate insulin is unavailable to maintain normal blood glucose levels.
• Hyperglycemia develops and diabetes is diagnosed after 80-90% of the beta cells are destroyed.
• Autoimmunity is a major factor in the pathophysiology of type 1 DM.

Type 2 DM Pathogenesis (Ominous Octet)

• Decreased insulin secretion is a key factor.
• There is a decreased incretin effect.
• Increased lipolysis occurs.
• Hyperglycemia is central to the pathogenesis.
• Increased glucose reabsorption is observed.
• Glucagon secretion increases.
• Hepatic glucose production (HGP) is increased.
• There is neurotransmitter dysfunction.
• Glucose uptake is decreased.

Classification of Diabetes Mellitus

• Type 1 diabetes includes both immunologically mediated and idiopathic forms.
• Type 2 diabetes is a distinct category.
• Other specific types include:
  • Genetic disorders of B-cell function (MODY, mitochondrial DNA).
  • Genetic disorders in insulin action (lipoatrophic diabetes).
  • Exocrine pancreas diseases (pancreatitis, hemochromatosis).
  • Endocrinopathies (acromegaly, Cushing's syndrome).
  • Drug-induced diabetes (glucocorticoids, thiazides).
  • Infections (cytomegalovirus, congenital rubella).
  • Uncommon immunological forms (insulin receptor antibodies).
  • Other genetic syndromes (Down, Turner, Prader-Willi syndrome).
• Gestational diabetes is another class.

Types of DM Comparison

• Type 1 typically presents in childhood and adolescence, while Type 2 predominantly occurs after age 40.
• Type 1 patients are often thin or normal weight, whereas Type 2 patients are often obese.
• Ketoacidosis is prone in Type 1 but not in Type 2.
• Insulin administration is essential for survival in Type 1, but not always required in Type 2.
• Pancreas damage in Type 1 is due to autoimmune attack; in Type 2, the pancreas is not damaged by an autoimmune attack.
• Type 1 involves absolute insulin deficiency, and Type 2 involves relative insulin deficiency and/or insulin resistance.
• Type 1 is treated with insulin injections; Type 2 is managed with diet, exercise, oral hypoglycemics, or insulin.
• Increased prevalence in relatives is noted in both types.
• Identical twin studies show lower concordance in Type 1 (<50%) than in Type 2 (above 70%).
• There is an HLA association in Type 1, but not in Type 2.

Clinical Picture of DM

• Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, and sometimes polyphagia.
• Blurred vision also indicate hyperglycemia.
• Impairment of growth may occur.
• Susceptibility to certain infections may accompany chronic hyperglycemia.
• Other signs are tiredness, lack of interest/concentration, numbness in the hands/feet, frequent infections, and slow-healing wounds.

Complications of DM

• Coma may result from diabetic ketoacidosis due to a combination of high blood sugar, dehydration, shock, and exhaustion.
• Coma often occurs after 36 hours of worsening vomiting and hyperventilation.
• Nonketotic hyperosmolar coma arises from extremely high blood sugar levels paired with dehydration from inadequate fluid intake; seen in type 2 or steroid diabetes patients.
• Lactic acidosis can occur.
• Hypoglycemia is a risk.

Microvascular Complications

• Diabetic retinopathy can occur.
• Diabetic nephropathy (DN) typically starts with microalbuminuria, progressing to overt albuminuria and eventually renal failure, making it the leading cause of end-stage renal disease.
• Diabetic neuropathy includes peripheral distal symmetrical polyneuropathy (predominantly sensory), autonomic neuropathy, proximal painful motor neuropathy, and cranial mononeuropathy (e.g., cranial nerve III, IV, or VI).

Macrovascular Complications

• Cerebrovascular disease, such as stroke, can arise.
• Peripheral artery disease involves occlusion of lower-extremity arteries, causing intermittent claudication/pain, foot ulceration, and lower-extremity amputation.
• Cardiovascular disease is common.
• Patients, especially with type 2 DM, often have risk factors like central obesity, dyslipidemia, and hypertension.
• There is a 5-fold greater risk for a first myocardial infarction (MI) and a 2-fold greater risk for a recurrent MI in individuals who have had an MI and also have diabetes.

Infections Related to DM

• Malignant otitis externa can occur.
• Tuberculosis
• COVID-19 infection is a risk.
• Rhinocerebral mucormycosis can develop.
• Bacteriuria is a risk.
• Pyuria, cystitis, and upper urinary tract infections are possible.
• Intrarenal bacterial infections can occur.
• Skin and soft tissue infections are likely.
• Osteomyelitis is also identified.

Diagnosis of DM

• American Diabetes Association (ADA)'s diagnostic criteria are:
  • Fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher.
  • A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT).
  • A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis.
  • Hemoglobin A1c (HbA1c) level of 6.5% or higher.
• Indications for diabetes screening in asymptomatic adults:
  • Sustained blood pressure >135/80 mm Hg.
  • Overweight and 1 or more other risk factors for diabetes (e.g., first-degree relative with diabetes, BP >140/90 mm Hg, and HDL < 35 mg/dL and/or triglyceride level >250 mg/dL).
  • Age of 45 years or older.

Tests to Differentiate Type 2 and Type 1 Diabetes

• Fasting C-peptide level of more than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes.
• Islet-cell (IA2), anti-GAD65, and anti-insulin autoantibodies can be present in early type 1 diabetes.

Management of DM

• Microvascular (i.e., eye and kidney disease) risk reduction through control of glycemia and blood pressure is key.
• Macrovascular (coronary, cerebrovascular, peripheral vascular) risk reduction through control of lipids and hypertension and smoking cessation.
• Metabolic and neurologic risk reduction through glycemia control.
• Dietary and exercise modifications.
• Medications may be necessary.
• Appropriate self-monitoring of blood glucose (SMBG) is important.
• Regular monitoring for complications is required.
• Regular laboratory assessment is needed.

DM Management Strategies

• Low carbohydrate intake.
• All patients on insulin should have a comprehensive diet plan created with a professional dietitian that includes:
  • A daily caloric intake prescription.
  • Recommendations for amounts of dietary carbohydrate, fat, and protein.
  • Instructions on how to divide calories between meals and snacks.
• Exercise promotes blood sugars.
• Rigorous exercise for more than 30 minutes may require either decreasing the preceding insulin injection by 10-20% or having an extra snack.

Regular Checkups for DM

• HbA1c should be checked every 3-6 months.
• Yearly dilated eye examinations are necessary.
• Annual microalbumin checks are needed.
• Foot examinations at each visit are important.
• Blood pressure should be < 130/80 mm Hg, though lower in cases of diabetic nephropathy.
• Statin therapy is used to reduce low-density lipoprotein cholesterol.

Pharmacologic Treatment of Hyperglycemia in Adults with Type 2 Diabetes

• First-line therapy depends on comorbidities, patient-centered treatment factors (including cost/access), and management needs.
• Metformin and comprehensive lifestyle modification are generally included.
• For patients at high risk, independent of baseline A1c, individualized A1c target, or metformin use:
  • Incorporate agents that provide adequate efficacy to maintain glycemic goals, such as GLP-1 RA, insulin, or combination approaches.
  • Consider comorbidities, patient-centered treatment factors, and management needs when choosing therapy.

Biguanides (Metformin)

• Decreases hepatic gluconeogenesis.
• Decreases intestinal absorption of glucose.
• Improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
• Adverse effects include gastrointestinal upset.
• Lactic acidosis is a concern.

Sulfonylureas

• Sulfonylureas (e.g., glyburide, glipizide, glimepiride) are insulin secretagogues that stimulate insulin release from pancreatic beta cells.
• These likely have the greatest efficacy for glycemic lowering of any of the oral agents.
• May also enhance peripheral sensitivity to insulin secondary to an increase in insulin receptors or to changes in the events following insulin-receptor binding.
• The main side effect is hypoglycemia.

Thiazolidinediones (TZDs)

• Selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ).
• Acts as insulin sensitizers.
• Side effects include fluid retention, increased bladder cancer risk, and osteoporotic fractures.

Glucagon-Like Peptide-1 (GLP-1) Agonists

• Examples include exenatide, liraglutide, albiglutide, and dulaglutide.
• Mimic the endogenous incretin GLP-1.
• Stimulates glucose-dependent insulin release.
• Reduces glucagon.
• Slows gastric emptying.
• In addition to metformin and/or a sulfonylurea, the may result in modest weight loss.
• Side effects include pancreatitis and medullary thyroid carcinoma.

Dipeptidyl Peptidase IV (DPP-4) Inhibitors

• Examples are sitagliptin, saxagliptin, and linagliptin.
• Prolong the action of incretin hormones.
• DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP).
• Weight neutral
• It can be used as a monotherapy or in combination with metformin or a TZD.
• Given once daily.

Selective Sodium-Glucose Transporter-2 (SGLT-2) Inhibitors

• SGLT-2 inhibition lowers the renal glucose threshold.
• The plasma glucose concentration exceeds the maximum glucose reabsorption capacity of the kidney.
• Lowering results in increased urinary glucose excretion.

Alpha-Glucosidase Inhibitors

• Alpha-glucosidase inhibitors prolong the absorption of carbohydrates.
• The induction of flatulence greatly limits their use.
• They should be titrated slowly to reduce gastrointestinal (GI) intolerance.

Indications for Insulin Use

• Type 1 DM
• Gestational diabetes
• DKA, hyperosmolar coma
• Uncontrolled type II DM (hyperglycemia with metabolic decompensation or A1C > 9%)

Types of Insulin

• Rapid-acting insulin analogues: onset 5-15 min, peak 30-60 min, duration 2-5 hr, injected at the start of a meal.
• Short-acting (soluble/regular insulin): onset 30 min, peak 1-3 hr, duration 4-8 hr, injected 15-30 minutes before a meal, clear solution.
• Intermediate or long-acting insulin (isophane or zinc insulin): onset 1-2 hr (NPH, Lente) or 2-3 hr (Ultralente), peak 4-8 hr, duration 8-12 hr (NPH) or 8-24 hr (Ultralente), used to control glucose levels between meals, combined with short-acting insulin.
• Long-acting insulin analogues: onset 30-60 min, no peak, duration 16-24 hr, usually taken once daily.

Select Initial Insulin Regimen Based on Patient Needs

• Background (basal) insulin (added to oral agents): used for patients feeling overwhelmed, fearful of injections, or with mostly elevated fasting BG, NPH recommended as first line.
• Premixed insulin: used for patients opposed to more than 2 injections a day, with consistent mealtimes and food intake, and elevated fasting and/or post-meal BG.
• Background (basal) and mealtime (bolus) insulin: used for patients desiring tight control and a flexible schedule and elevated fasting and/or post-meal BG, NPH recommended for basal and regular insulin suggested for bolus as first line.

Insulin Regimens and Dosing

• Background (basal) insulin (added to oral agents):
  • Starting dose: 5 to 10 units (0.1 to 0.2 units/kg/daily).
  • Start with one dose at bedtime
  • Starting dose 10 units at bedtime, increase dose by 1 unit every night until FBG = 4 to 7 mmol/L
• Premixed insulin:
• Start with 2 doses: before breakfast and before supper
• Starting dose: 5 to 10 units twice daily (0.1 to 0.2 units/kg twice daily).
• 10 units ac breakfast, 10 units ac supper, increase breakfast dose by 1 unit every 1 day until pre-supper BG = 4 to 7 mmol/L; increase supper dose by 1 unit every 1 day until FBG = 4 to 7 mmol/L
• Background (basal) and mealtime (bolus) insulin:
  • Calculate TDI dose as 0.3 to 0.5 units/kg, then distribute as follows: 40% TDI as basal insulin at bedtime, 20% TDI as bolus insulin prior to each meal
• Initially, mealtime insulin dose is divided evenly between meals
• For an 80-kg person: TDI = 0.5 units/kg = 0.5 x 80. TDI = 40 units; Basal insulin = 40% of TDI = 40% x 40 units: Basal insulin = 16 units, Bolus insulin = 60% of TDI = 60% x 40 units Bolus = 24 units = 8 units with each meal

Insulinoma Overview

• These are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism.
• Approximately 90-95% of insulinomas are benign.
• Long-term cure with total resolution of preoperative symptoms is expected after complete removal.

Signs and Symptoms of Insulinoma

• Whipple triad, presence of symptoms of hypoglycemia (about 85% of patients)
• Documented low blood sugar
• Reversal of symptoms by glucose administration
• Neurogenic: Diplopia, Confusion, Abnormal behavior, Unconsciousness Amnesia Seizures
• Neuroglycopenic symptoms: sweating, tachycardia, palpitations, and hunger

Diagnosis of Insulinoma - Lab Studies

• Failure of endogenous insulin secretion to be suppressed by hypoglycemia is the hallmark of an insulinoma, presence of inappropriately elevated levels of insulin in the face of hypoglycemia diagnosis.
• Biochemical diagnosis of insulinoma is established in 95% of patients during prolonged fasting (up to 72 h) when results that are found are:
  • Serum insulin levels of 10 μU/mL or more (normal < 6 μU/mL)
  • Glucose levels of less than 40mg/dL
  • C-peptide levels exceeding 2.5 ng/mL (normal < 2 ng/mL)
  • Proinsulin levels greater than 25% (or up to 90%) of immunoreactive insulin levels
  • Screening for sulfonylurea negative

Diagnosis of Insulinoma - Imaging studies

• Endoscopic ultrasonography
• Real-time transabdominal high-resolution ultrasonography
• Computed tomography (CT) scanning
• Magnetic resonance imaging (MRI)
• Selective arterial calcium stimulation (SACST) with hepatic venous sampling
• PET/CT with gallium-68 DOTA-(Tyr3)-octreotate (Ga-DOTATATE)

Management of Insulinoma

• Pharmacologic therapy and is designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden:
  • Diazoxide: It Reduces insulin secretion
  • Somatostatin analogs (octreotide, lanreotide): Prevent hypoglycemia
• Surgery