Diabetes & Its Complications

BCH 130 β€” Advanced Human Biochemistry Β· Dr. Radi

build Jul 18 Β· 08:24 Β· CC BY-NC-SA 4.0 Β· owned figures (RDKit / matplotlib)
Dr. Radi

By the end of this unit, you can…

  • Contrast the pathophysiology of type 1 (beta-cell loss, absolute insulin deficiency, ketosis-prone) and type 2 diabetes (insulin resistance + progressive beta-cell failure).
  • Describe beta-cell biology and its failure
  • Explain the counter-regulatory hormone response and why unopposed glucagon drives hyperglycemia and ketogenesis in insulin deficiency.
  • Interpret the diagnostic tests β€” fasting glucose, OGTT, HbA1c (with its biochemistry and pitfalls), C-peptide, and islet autoantibodies β€” to distinguish diabetes types.
Dr. Radi

Today's route πŸ—ΊοΈ

  1. Type 1 vs Type 2 β€” Two Roads to Diabetes
  2. Diagnosing Diabetes β€” Reading the Labs
  3. The Other Diabetes β€” Monogenic & Secondary
  4. Diabetic Complications β€” Where the Sugar Does Its Damage
Dr. Radi

1 Β· Type 1 vs Type 2 β€” Two Roads to Diabetes

"Same diagnosis, two completely different diseases. Type 1 is a destruction story β€” the Ξ²-cells are gone and insulin drops to zero. Type 2 is a resistance story β€” insulin is loud but ignored, until the exhausted Ξ²-cells finally quit. Name the mechanism first, and the labs, the ketones, and the treatment all fall into place."

Dr. Radi

Two diseases, one name

Don't let the shared label fool you. Type 1 is a destruction story β€” the Ξ²-cells are gone, insulin falls to zero, and with nothing to restrain fat breakdown it runs to ketones (ketosis-prone). Type 2 is a resistance story β€” insulin is high but ignored, until overworked Ξ²-cells progressively fail. Opposite mechanisms, same hyperglycemia.

Dr. Radi

How the Ξ²-cell knows

How does a Ξ²-cell sense that glucose is high? GLUT2 lets glucose flood in, and glucokinase β€” a sensor tuned to the physiologic range β€” sets the pace. Burning it raises ATP, which slams the KATP channel shut, depolarizes the cell, opens Ca²⁺, and releases insulin. Gut incretins amplify every meal.

Dr. Radi

When the Ξ²-cell burns out

So why do Type 2 Ξ²-cells eventually quit? Three insults gang up. IAPP amyloid deposits choke the islet. Glucotoxicity β€” chronic high glucose β€” poisons the very cells meant to fix it. And lipotoxicity from spilled fatty acids finishes them off. That's why Type 2 is progressive: the insulin factory slowly wears out.

Dr. Radi

The unopposed glucagon problem

Here's the twist students miss: insulin deficiency isn't just low insulin β€” it unleashes glucagon. Normally insulin restrains the Ξ±-cell; remove that brake and glucagon runs wild. The liver obeys, pouring out glucose and ketone bodies. That's exactly why absolute insulin loss tips straight into ketoacidosis.

Dr. Radi

2 Β· Diagnosing Diabetes β€” Reading the Labs

"Three numbers make the diagnosis, two more tell you which type, and one β€” HbA1c β€” is a beautiful piece of biochemistry that occasionally lies to you. Let's learn to read the panel like a biochemist: what each test measures, where the cut-offs sit, and when to trust the A1c and when to reach for something else."

Dr. Radi

Three ways to make the call

You can diagnose diabetes three ways, and any one clinches it: fasting glucose β‰₯ 126, a 2-hour OGTT β‰₯ 200 after a 75 g load, or HbA1c β‰₯ 6.5%. A random glucose β‰₯ 200 plus classic symptoms counts too. Sitting just below each cut-off? That's prediabetes β€” the warning shot.

Dr. Radi

Which type is it?

The diagnosis is diabetes β€” but which type? Two tests settle it. C-peptide is released 1:1 with your own insulin, so low means Type 1 (nothing left) and normal-to-high means Type 2 (plenty, just ignored). Islet autoantibodies (GAD65, IA-2) present? That flags the autoimmune, Type 1 process.

Dr. Radi

HbA1c is built, not measured

HbA1c isn't a level β€” it's built. Glucose drifts onto hemoglobin's N-terminus with no enzyme, forming a wobbly Schiff base that rearranges (the Amadori step) into a stable ketoamine. Because red cells live ~120 days, that sugar-coating records your average glucose over 2–3 months. Elegant, right?

Dr. Radi

When A1c lies to you

A1c has a blind spot: it trusts the red cell's clock. Shorten that lifespan β€” hemolysis, bleeding, pregnancy, EPO β€” and there's less time to glycate, so A1c reads falsely low. Lengthen it β€” iron deficiency, splenectomy β€” and it reads falsely high. And hemoglobinopathies fool the assay entirely.

Dr. Radi

3 Β· The Other Diabetes β€” Monogenic & Secondary

"Not every diabetic is Type 1 or Type 2. Sometimes it's a single broken gene that tells you exactly which pill to prescribe; sometimes it's pregnancy, a wrecked pancreas, or another hormone bullying insulin. Learn to spot these, because the label changes the treatment β€” and occasionally cures it."

Dr. Radi

One gene, one diagnosis

Sometimes diabetes is one broken gene, and the gene dictates the fix. GCK MODY is mild and stable β€” often needs nothing. HNF1A/4A MODY and KATP neonatal diabetes respond beautifully to sulfonylureas β€” not insulin! And mitochondrial diabetes travels with deafness down the maternal line. Genotype, not glucose, guides treatment.

Dr. Radi

Diabetes by another route

Not every diabetic fits the big two. LADA is slow autoimmune diabetes in adults β€” it masquerades as Type 2 until the antibodies surface. Gestational diabetes rides pregnancy's built-in insulin resistance. And pancreatogenic (type 3c) diabetes follows a destroyed pancreas β€” losing insulin and glucagon at once.

Dr. Radi

Hormones that cause diabetes

Whole hormones can cause diabetes by fighting insulin. Pile on glucocorticoids β€” a steroid prescription or Cushing's cortisol β€” and glucose climbs. Acromegaly's growth hormone and a pheochromocytoma's catecholamines do the same. Each drives insulin resistance plus hepatic glucose output. Fix the source and the diabetes often melts away.

Dr. Radi

4 Β· Diabetic Complications β€” Where the Sugar Does Its Damage

"This is why we fight so hard for control. Chronic high glucose isn't just a number β€” it's a slow poison that fans into four biochemical pathways and cashes out as blindness, kidney failure, numb feet, and early heart attacks. And when insulin runs out fast, the emergencies arrive: DKA and HHS. Let's connect the biochemistry to the bedside."

Dr. Radi

One poison, four pathways

Why does high glucose damage tissue? In cells that can't throttle uptake β€” nerve, retina, kidney β€” glucose floods in and fans into four pathways: the polyol shunt (burning NADPH), AGE/RAGE glycation, PKC activation, and the hexosamine route. One upstream culprit unifies them: mitochondrial superoxide.

Dr. Radi

From pathways to complications

Those pathways cash out as complications. Microvascular damage blinds the eye (retinopathy), scars the kidney (nephropathy), and numbs the feet (neuropathy). Macrovascular disease is accelerated atherosclerosis β€” why diabetics suffer heart attack and stroke years early. Tight glucose control delays all of it.

Dr. Radi

DKA vs HHS: the two crises

Two emergencies, one spectrum. DKA hits when insulin reaches zero (usually Type 1): fat burns to ketones, blood turns acidic β€” an anion-gap acidosis. HHS is just enough insulin to block ketones but not glucose (usually Type 2): sugar soars past 600, turning hyperosmolar.

Dr. Radi

Can you…?

  • ☐ contrast the pathophysiology of type 1 (beta-cell loss, absolute insulin deficiency, ketosis-prone) and type 2 diabetes (insulin resistance + progressive beta-cell failure).?
  • ☐ describe beta-cell biology and its failure?
  • ☐ explain the counter-regulatory hormone response and why unopposed glucagon drives hyperglycemia and ketogenesis in insulin deficiency.?
  • ☐ interpret the diagnostic tests β€” fasting glucose, OGTT, HbA1c (with its biochemistry and pitfalls), C-peptide, and islet autoantibodies β€” to distinguish diabetes types.?

If any box stays empty, the practice site has a drill for it. πŸ§ͺ

Dr. Radi