Diabetes I: Beyond Gestational DM

What is diabetes?

  • Diabetes is a Greek word meaning siphon - to pass through.

    • Mellitus, which is the common form we think of, is a Latin word meaning “sweet.” 

    • Insipidus, which is another form of diabetes we won’t talk about today, is a Latin word meaning “tasteless.” 

      • These terms refer to the effect of the disease on the urine, where mellitus is the passage of glucose through urine, making it sweet; while insipidus is unregulated water passing through urine, making it dilute.

  • Diabetes mellitus:

    • Around 8.8% of the world’s population has diabetes mellitus.

    • There are two main types.

      • Type 1 DM: this refers to a deficiency of insulin (10-15% of those with DM)

      • Type 2 DM: this refers to a resistance to insulin (85-90% of those with DM)

Type 1 Diabetes 

  • Insulin deficiency 

    • Thought to be primarily related to an autoimmune process leading to loss of pancreatic beta-cells.

  • Previously referred to as “juvenile diabetes” owing to predilection for onset in childhood:

    • 90,000 children diagnosed each year worldwide

    • Most common form of diabetes in those under age 15

      • Peak incidence at 12-14 years of age.

  • Has geographic predilection for Scandinavia, Europe, North America, and Australia. Incidence:

    • Over 10/100k in Europe, Russia, USA, Canada, Australia

    • Relatively rare in Asia - China, India, Middle East all <5/100k

  • Clinical onset of diabetes is marked by hallmark symptoms, and these are ultimate reason for diagnosis in >95% of cases:

    • Polydipsia (increased thirst)

    • Polyuria (increased urination)

    • Weight loss

    • Abdominal pain

    • Ketoacidosis (previous podcast!)

  • Given the insulin deficiency, treatment revolves around replacement of insulin with synthetic forms.

    • No successful studies thus far with immunologic interventions or preventive therapies.

Type 2 Diabetes

  • Acquired insulin resistance

    • This operates in three ways of pathophysiology:

      • Peripheral tissue insulin resistance: 

        • Overactivation of peripheral insulin receptors leads to downregulation - tissues are overextended.

      • Pancreatic beta cell dysfunction: 

        • Beta cells churning out loads of insulin - they get tired and “wear out.” 

      • Pancreatic alpha cell function increasing:

        • Hypothesized that the bar for hypoglycemia is raised physiologically - so inappropriate, early secretion of glucagon keeping blood sugars high.

    • T2DM’s insulin resistance is similar to gestational diabetes mellitus, where secretion of human placental lactogen creates an adaptogenic resistance to insulin (increasing glucose availability from the fetal perspective).

  • T2DM has a high prevalence worldwide, and is increasing.

    • A global pandemic of metabolic disease?!

      • Some estimate over 590 million worldwide will be affected by 2035.

      • Increasing prevalence worldwide, but most notable in US, Asia-Pacific, North Africa.

    • Highly associated with obesity - 90% of patients are obese or overweight at diagnosis.

      • Excess energy consumption combined with insufficient energy expenditure.

      • Generally adult-onset, but increasing prevalence in younger populations particularly with comorbid obesity.

  • Clinical onset is not typically acute:

    • Prediabetes often is manifest in these patients before diagnosis

      • 5-10% progress from prediabetes to T2DM annually.

      • Can be manifest for years-decade before progression.

    • Can manifest with similar acute symptoms to T1DM, but is most commonly insidious.

      • May be diagnosed incidentally with other healthcare-seeking, particularly major metabolic disease events (MI, stroke) or in seeking unrelated care (i.e., surgeries).

      • Common less acute presentations can include:

        • Fatigue, malaise

        • Infections (i.e., recurring genitourinary candidiasis)

        • Blurred vision

Some other, rarer forms of diabetes mellitus:

  • Latent autoimmune diabetes in adults (LADA) - a special type of DM that shares features with T1 and T2DM

    • Some may refer to this as “type 1.5” because of the mixed features:

      • Does not require insulin therapy for the first six months after diagnosis.

      • Typically acquired after age 35

      • Autoimmunity of T1DM - identifiable autoantibodies against pancreatic beta cells.

    • Depending on the stage in which they are identified or treated in their disease course, they may be responsive to oral insulin-sensitizing medications, or may require insulin.

  • Maturity Onset Diabetes of the Young (MODY) - hereditary form of DM with disruption of insulin production.

    • Typically an autosomal dominant inheritance:

      • Affected individuals have a 50% chance of passing to offspring.

    • Depending on the affected gene, hyperglycemia may be mild or severe, and treatment depends on which form of MODY a patient has.

    • Must be diagnosed before age 25.

  • Cystic fibrosis associated diabetes - given the failure of the exocrine pancreas in CF, most patients will develop a T1DM-like diabetes over time.

    • As therapies have gotten better for CF, some patients also develop T2DM features.

  • Steroid-associated diabetes - given hyperglycemia-inducing effects, those on chronic steroid therapy can develop diabetes akin to type 2 diabetes.

Diagnosing Diabetes Mellitus

  • Type 1 and type 2 diabetes 

    • Diagnosed according to the same ADA criteria for diabetes - one or more of:

      • Fasting glucose of > 126 mg/dL (with fasting defined as no caloric intake for at least 8 hours).

      • Glucose of > 200 mg/dL on a 2 hour, 75g oral glucose tolerance test (OGTT).

      • Hemoglobin A1c of > 6.5%.

      • Random glucose of > 200 mg/dL in a patient with classic hyperglycemia symptoms.

  • Prediabetes 

    • Diagnosed with any of the following:

      • Hemoglobin A1c of 5.7 - 6.4%.

      • Glucose of 140-199 mg/dL on a 2 hour, 75g OGTT.

      • Fasting glucose of 100-125 mg/dL

Complications of Diabetes

  • Acute

  • Chronic

    • Most of the major complications of diabetes that we think about result from chronic disease.

    • Many of the complications are due to microangiopathy, or damage to smallest blood vessels.

      • Excess blood glucose likely leads to incorporation of the excess sugar within capillary basement membranes.

      • This incorporation of excess sugar weakens the basement membranes, making them prone to micro-aneurysms.

      • When the microaneurysms rupture, new vessels and connective tissue must form, which causes sclerosis and narrowing of the arterioles surrounding the capillary.

      • This overall leads to worsened tissue perfusion and tissue function, and ultimately systemic hypertension.

    • Microangiopathy shows up everywhere:

      • Nephropathy

        • Damage to the renal glomeruli (capillaries of the kidney involved in filtration) worsen their filtering ability → glucosuria → microalbuminuria → CKD, renal failure, dialysis.

      • Neuropathy

        • Damage to the small vessels leading to nerve endings ultimately starves them of oxygen, impairing sensation.

          • This tends to develop in a “stocking and glove” form, affecting most distal extremities (smallest capillaries).

      • Retinopathy

        • Damage to small vessels in the retina, with growth of poor quality small new blood vessels (proliferative retinopathy) → macular edema → blindness 

          • Diabetic retinopathy is the most common cause of blindness among non-elderly adults in the world.

      • Sexual and reproductive dysfunction

        • Damage to small vessels leads to decreased sensation in women (and erectile dysfunction in men).

        • Infertility is more prevalent in patients with type 1 diabetes.

        • PCOS / oligo-ovulatory states are linked with insulin resistance and diabetes.

      • Encephalopathy

        • Linkage of diabetes and microvascular changes in the brain to cognitive decline, dementia.

    • Ultimately, this microangiopathy will contribute to the development of macroangiopathy, affecting larger blood vessels and complications such as:

      • Coronary artery disease → angina, myocardial infarction

      • Peripheral vascular disease → claudication, diabetic foot → amputation

      • Ischemic strokes

      • Hypertension