Learn: Diabetes Detailed

What are the 3 classic manifestations of diabetes?

Polydipsia, polyuria, and polyphagia.

What is polydipsia?

Constant thirst.

What is polyuria?

Frequent urination.

What is polyphagia?

Excessive hunger/lack of weight gain despite a healthy appetite.

What A1C level meets the diagnostic criterion for diabetes?

A1C ≥ 6.5%.

What fasting plasma glucose (FPG) meets the diagnostic criterion for diabetes?

FPG ≥ 126 mg/dL (7.0 mmol/L).

What 2-hour glucose level during an OGTT meets the diagnostic criterion for diabetes?

2-hour postprandial plasma glucose ≥ 200 mg/dL (11.1 mmol/L).

What random plasma glucose meets the diagnostic criterion when classic hyperglycemia symptoms are present?

Random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia.

What causes hyperglycemia in diabetes?

Lack of insulin or insulin resistance.

What happens to glucose uptake in insulin-dependent tissues during diabetes?

Glucose uptake decreases, especially in skeletal muscle and adipose tissue.

What happens to glycogen synthesis in diabetes?

Glycogen synthesis decreases.

How does diabetes increase gluconeogenesis?

There is increased conversion of amino acids to glucose through gluconeogenesis.

What is glucosuria?

The presence of excess glucose in the urine because blood glucose exceeds the renal threshold.

How can diabetes lead to ketoacidosis?

Increased fatty-acid mobilization and oxidation produces ketone bodies, which can lead to metabolic ketoacidosis.

What happens to glucagon in diabetes despite high blood glucose?

Glucagon levels remain inappropriately high (uninhibited glucagon).

What are the major cardiovascular complications of diabetes listed in the notes?

Microangiopathies and macroangiopathies.

How does hyperglycemia contribute to diabetic neuropathy?

It increases flux through the polyol pathway via aldose reductase, causing intracellular sorbitol/water accumulation and oxidative neuronal damage.

What renal changes are associated with diabetic nephropathy?

Renal vascular lesions and thickening/changes of the glomerular basement membrane.

What ocular complications are associated with diabetes?

Cataracts, retinal microaneurysms, and hemorrhages.

Why are people with diabetes more susceptible to infections?

Diabetes increases susceptibility to bacterial and fungal infections.

Approximately what percentage of the diabetic population has type 1 diabetes?

About 10%.

What is the primary cause of type 1 diabetes?

Near-complete destruction of pancreatic β-cell mass through an autoimmune response.

Is type 1 diabetes associated with absolute or relative insulin deficiency?

Absolute insulin deficiency/dependency.

What is the typical age of onset for type 1 diabetes in the notes?

Early age; mean age is approximately 12 years.

What acute metabolic complication is type 1 diabetes prone to?

Diabetic ketoacidosis (DKA).

Is family history often positive in type 1 diabetes?

No. Family history is often negative.

What are the major autoantibodies/markers associated with type 1 diabetes?

Islet cell antibodies (ICA), insulin autoantibodies (IAA), GAD65, and IA-2.

What are the sensitivity and specificity values listed for IA-2?

57% sensitivity and 99% specificity.

• 57% of non-diabetics who have it will develop type 1 diabetes

•  99% of Type 1 diabetics have Abs

What does C-peptide indicate in a patient receiving injected insulin?

It serves as a marker of endogenous insulin secretion.

What percentage of diabetics is listed as having non-obese type 2 diabetes?

About 10%.

What percentage of diabetics is listed as having obese type 2 diabetes?

About 80%.

What age of onset is associated with non-obese type 2 diabetes in the notes?

Often under 25, including MODY.

What age of onset is associated with obese type 2 diabetes in the notes?

Usually over 35 (adult onset).

Is family history common in both non-obese and obese type 2 diabetes?

Yes; the notes list family history as present for both.

How is insulin secretion described in non-obese type 2 diabetes?

Low.

How is insulin secretion described in obese type 2 diabetes?

Low for body mass.

What is the pathophysiology of non-obese type 2 diabetes in the notes?

Mutations in specific proteins and decreased β-cell mass.

What is the pathophysiology of obese type 2 diabetes in the notes?

Insulin resistance and relative insulin deficiency.

What is insulin's overall role in metabolism?

Insulin is the primary anabolic hormone.

What does insulin do in the liver?

Inhibits glycogenolysis, gluconeogenesis, and ketogenesis; stimulates glycogen and triglyceride synthesis.

What does insulin do in skeletal muscle?

Stimulates glucose transport and amino-acid transport/protein synthesis.

What does insulin do in adipose tissue?

Stimulates triglyceride storage and glucose transport.

Where is glucagon secreted?

Pancreatic α-cells.

What does glucagon do?

Promotes glycogen breakdown, increases hepatic gluconeogenesis, and elevates blood glucose.

Where is somatostatin secreted?

Pancreatic δ-cells.

What is somatostatin's role in the pancreas?

It is a general paracrine inhibitor of both insulin and glucagon secretion.

What is amylin also called?

Islet amyloid polypeptide (IAPP).

How is amylin released relative to insulin?

It is co-secreted 1:1 with insulin from β-cells.

What does amylin do?

Slows gastric emptying, suppresses postprandial glucagon release, and decreases food intake.

During fasting, what percentage of glucose uptake is non-insulin-dependent?

About 75%.

During fasting, what percentage of glucose uptake is insulin-dependent?

About 25%, primarily involving skeletal muscle.

Which tissues account for the major non-insulin-dependent glucose uptake during fasting?

Brain, GI tract, and liver.

What is glucagon doing during the fasting state?

It is active to help prevent hypoglycemia.

During the fed/prandial state, what percentage of glucose disposal occurs in skeletal muscle?

About 80-85%.

During the fed/prandial state, what percentage of glucose disposal occurs in adipose tissue?

About 4-5%.

What does insulin do to glucagon secretion after a meal?

Suppresses glucagon secretion.

What does insulin do to free-fatty-acid release from adipocytes?

Reduces FFA release.

Where is GLUT1 widely expressed?

It is constitutively expressed and widely distributed, including the brain and RBCs.

What is the approximate Km of GLUT1 and what does it indicate?

Km 1-6 mM; low Km means high affinity for glucose.

Where is GLUT2 expressed?

Pancreatic β-cells, liver, intestine, and kidney.

What is the approximate Km of GLUT2 and what does it indicate?

Km 15-20 mM; high Km means relatively low affinity and makes it useful as a glucose sensor.

Where is GLUT3 expressed?

Neurons/brain.

What is the approximate Km of GLUT3?

Km

Where is GLUT4 expressed?

Skeletal muscle, cardiac muscle, and adipocytes.

What is the approximate Km of GLUT4?

About 5 mM.

What is unique about GLUT4 regulation?

Insulin induces GLUT4 translocation to the cell membrane.

How does glucose enter pancreatic β-cells according to the notes?

Through GLUT transporters; GLUT1 in humans and GLUT2 in rodents.

What enzyme phosphorylates glucose in the β-cell?

Glucokinase.

What is the role of glucokinase in β-cells?

It catalyzes the rate-limiting step of glucose metabolism.

What happens to glucose after phosphorylation in the β-cell?

It undergoes glycolysis and mitochondrial respiration.

What happens to the ATP/ADP ratio when β-cell glucose metabolism increases?

The intracellular ATP/ADP ratio increases.

What channel closes when the β-cell ATP/ADP ratio rises?

ATP-sensitive potassium (KATP) channels.

What happens to the β-cell membrane when KATP channels close?

The membrane depolarizes.

What happens after β-cell depolarization?

Voltage-gated Ca2+ channels open, causing Ca2+ influx.

What triggers insulin granule exocytosis?

Elevated cytosolic Ca2+.

What happens to proinsulin?

It is cleaved into insulin and C-peptide.

What is the role of Zn2+ in insulin storage?

Zn2+ coordinates insulin monomers into stable hexamers in dense-core granules.

Which transporter mediates the zinc-related insulin granule process?

ZnT8.

What is the structure of the insulin receptor?

A heterotetrameric α2β2 complex with two α and two β subunits linked by disulfide bonds.

What is the role of the insulin receptor α-subunits?

They are extracellular regulatory subunits that bind insulin.

What do α-subunits do in the basal state?

They repress the intrinsic tyrosine-kinase activity of the β-subunits.

What happens when insulin binds the insulin receptor?

Insulin binding relieves α-subunit repression, causing a conformational change and β-subunit autophosphorylation.

What is the role of the insulin receptor β-subunits?

They are transmembrane units containing intracellular tyrosine-kinase catalytic domains.

What does the IRS/PI3K/Akt pathway promote?

GLUT4 translocation, glycogen synthesis, protein synthesis, lipogenesis, and inhibition of gluconeogenesis.

What does the MAPK/Ras/Shc pathway regulate?

Cell growth, gene expression, and proliferation.

What is the onset of insulin lispro?

About 15 minutes.

What are the peak and duration of lispro?

Peak 0.5-1.5 hours; duration 6-8 hours.

What structural change makes lispro rapid-acting?

ProB28 and LysB29 are reversed, reducing self-association and favoring monomers.

What is the onset, peak, and duration of insulin aspart?

Onset 15 minutes; peak 1-3 hours; duration 3-5 hours.

What structural change makes aspart rapid-acting?

ProB28 is substituted with aspartate, destabilizing hexamers.

What is the onset, peak, and duration of insulin glulisine?

Onset 15 minutes; peak 0.5-1.5 hours; duration 3-5 hours.

What structural changes are present in glulisine?

AsnB3 is substituted with Lys and LysB29 with Glu, reducing aggregation.

What is the onset, peak, and duration of regular insulin?

Onset 30-60 minutes; peak 2-4 hours; duration 8-12 hours.

What is the structural form of regular human insulin before dissociation?

A zinc-stabilized hexamer that dissociates into dimers and then monomers.

What is the onset, peak, and duration of NPH insulin?

Onset 1-1.5 hours; peak 4-12 hours; duration about 24 hours.

What makes NPH insulin intermediate-acting?

It forms a crystalline complex with protamine; proteolytic enzymes slowly break down the protamine.

What are the onset, peak, and duration of glargine?

Onset 1-1.5 hours; essentially peakless; duration >24 hours.

What structural modifications are present in glargine?

AsnA21 is changed to Gly, with two Arg residues added to the B-chain C-terminus.

Why does glargine form a depot after injection?

It is soluble at pH 4.0 but microprecipitates at physiologic pH 7.4.

What are the onset, peak, and duration of insulin degludec?

Onset about 1 hour; peak about 9 hours; duration >24 hours.