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).
Review our GDM episodes: originals with Dr. Coustan and our last update.
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
Diabetic ketoacidosis and the related condition, hyperosmolar nonketotic coma, are emergencies that need to be treated!
In type 1 diabetes in particular, hypoglycemia also represents an emergency!
Can lead to coma, seizures, brain injury, death.
Treat with sugar - oral if possible, or IV.
Glucagon can also be used to prompt glucose release and hepatic gluconeogenesis.
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