Diabetes Mellitus

Normal Regulation of Glucose Metabolism

Insulin – tightly regulates plasma glucose between 60-110 mg/dl during fasting

acts on Liver, Muscle, and Adipose tissue-ß gluconeogenesis, Ý glucose transport, ß proteolysis, ß lipolysis – effects:

(1) increase glucose permeability to muscle and adipose cells for glycogen and triglyceride storage
(2) activate glycogen synthesis
(3) inactivate glycogenolysis, gluconeogenesis, and glucose release in liver
(4) inactivate ketogenesis
(5) suppress glucagon

Synthesis – insulin is synthesized in b cells of the Islets of Langerhans in pancreas as pro-insulin

pro-insulin is made into insulin in the Golgi by proteolytic cleavage of an intervening connecting peptide (C-peptide)
since C-peptide is secreted with insulin into the plasma and does not bind insulin receptors, it is a good lab measurement for the amount of insulin produced (recall that the liver extracts 50% of insulin from portal vein)

Secretion – serum glucose load and GI hormones (gastric inhib. peptide, glucagon-like peptide) stimulate insulin secretion

in healthy individuals, serum insulin is proportional to serum glucose

Glucagon – acts on Liver to stimulate glycogen breakdown, gluconeogenesis, and release of free glucose into blood

glucagon is usually inappropriately high in Type I diabetes

Normal Response to Serum Glucose Load:

Ý Insulin, ß Glucagon: allows the body to normalize glucose levels in the blood by using and storing glucose in the tissues

ß adrenergic stimulation from hypothalamus via portal sensor

Type 1 Diabetes Mellitus

10% of all cases of diabetes mellitus

Pathophysiology – destruction of b cells (unknown mechanism – see Etiology below) – a cells and d cells remain

result: absolute insulin deficiency – no insulin even with IV glucose, aa, b -adrenergic agonists, tolbutamide, etc.

four effects:

(1) glucose metabolism – Ý hepatic glucose output, ß peripheral glucose uptake/storage/oxidation

leads to hyperglycemia (due to gluconeogenesis)

peripheral glucose use can remain approximately normal despite ß insulin due to mass action

glucosuria – glucose in urine, since kidney can only reabsorb filtered glucose < 200 mg/dl

osmotic diuresis – glucose in renal tubules is osmotically active and this limits H₂O reabsorption

electrolyte imbalance – increase in plasma osmolality leads to migration of H₂O and K⁺ out of the cells (H⁺ enters cells in exchange for K⁺ Þ increases buffering capacity)

fasting blood sugar can reach 250-300 mg/dl, up to 600 mg/dl after meals – renal excretion limits it

reduction in fluids (vomiting, diarrhea) leads to ß GFR Þ exponential Ý in plasma glucose, ketones

(2) adipose metabolism – ß lipogenesis, ß adipose tissue mass, Ý acceleration of lipolysis

(3) ketoacid metabolism – Ý b -OH butyrate due to Ý lipolysis

ketoacids lead to metabolic acidosis (ß pH, ß pCO₂ (compensatory), ß HCO₃); use of Na⁺ and K⁺ to buffer acids leads to electrolyte imbalances

ketonuria – acetate and acetoacetate can be excreted in urine

no "peak" as with glucose, so can easily rise to fatal levels in Diabetic Ketoacidosis

(4) protein metabolism – increased proteolysis as amino acids are released for gluconeogenesis

leads to decreased growth and development, decreased lean body mass, greater fatigue

Epidemiology – usually appears before age 30 (peak incidence 9-14)

annual incidence is 13 per 100,000, with a prevalence of 0.3% – varies widely in different countries/ethnicities
type 1 diabetics have a tenfold increase in mortality over a non-diabetics

Clinical Presentation – patients are generally underweight

decreased weight due to high catabolic state Þ caloric drain via glucosuria and increased metabolic rate

intake of food is normal or increased since insulin no longer inhibits neuropeptide Y (appetite-stimulating peptide)

Ý thirst (polydipsia), Ý urination (polyuria), dehydration, weakness, fatigability, irritability, hepatomegaly (fatty infiltrate)

blurred vision – swelling of lens alters refraction; cataracts. NOT CURABLE!!

infection (pharyngitis, gastroenteritis, appendicitis) or stress (excess secretion of insulin antagonistic hormones – epinephrine, glucagon, cortisol, growth hormone) Þ accelerates metabolic and clinical decomposition

Histology – process of gradual b cell destruction – however, diagnosis is usually made before all b cells are gone

"Honeymoon period" – initial treatment brings a period of remission – b cell function returns somewhat (see C-peptide)

Etiology – unknown, but probably involves genetics, autoimmunity, and b cytotoxic agents (viruses, drugs)

(1) genetics – many candidate genes – having an identical twin with the disease increases risk

95% of type 1 diabetics have either HLA-DR3 or HLA-DR4 (MHC class II) – b cells express DR antigens

(2) autoimmune destruction – probably cell mediated cytotoxicity (CD8)

often Ý level of activated lymphocytes at diagnosis; T-cells and IL-1 have been found to inhibit insulin secretion

deficient T-cell suppressor function Þ autoantibodies to b cell antigens

autoantibodies form to insulin, glutamic acid decarboxylase (GAD), carboxypeptidase H
antibody presence is the best way to estimate risk

transfer of T cells can transfer the disease in laboratory animals

most important: immunosuppresion (cyclosporin) can improve b -cell function (Ý insulin)

(3) b-cytotoxic agents – probably viral infection – diabetics are genetically susceptible (coxsackie B3, hep, mono, etc.)

b-cytotoxic drugs are capable of inducing b -cell destruction (alloxan, streptozotocin, Vacor(rodenticide))

Type 2 Diabetes Mellitus

90% of all cases of diabetes mellitus

Pathophysiology – hyperglycemia sufficient to cause pathological changes in muscle and adipose

two causes:

(1) insulin resistance (hallmark of the disorder) – leads to inefficient insulin utilization by muscle and adipose tissue

(2) ß insulin secretion – abnormality in timing of insulin release Þ overproduction of glucose by liver

ß muscle glucose transport, ß glucose conversion to glycogen, Ý FFA, Ý VLDL, LDL; ß HDL; Ý glucagon

no excessive ketogenesis – enough insulin is still secreted to prevent ketoacid formation

Note: diabetic ketoacidosis can occur in type 2 diabetics after an insult (infection, etc.) that Ý hormones that counter insulin

hyperinsulinemia is seen early on (esp in obesity which causes insulin resistance), then declines later on

Glucose toxicity – high glucose levels impair insulin action on tissues and impair insulin secretion in b cells

very responsive to therapy – aggressive treatment can improve the disease, allowing less aggressive treatment

Sulfonylurea drugs – close ATPase K+ channel in b cell stimulating insulin release

Clinical Presentation – patients tend to be obese (Ý adipose tissue / lean body mass)

Age > 30 (peak incidence 6^th-8^th decade)
since glucose homeostasis is in steady state, onset is slow and insidious, and pathology can be clinically undetectable
polyuria and polydipsia (due to hyperglycemia and glucosuria)

Cardiovascular Effects – 75% of type 2 diabetics die of cardiovascular disease – related to severity of hyperglycemia

increased triglyceride, small dense LDL particles, apoB, and LDL; lowered HDL – atherosclerosis
increased fatty acid worsens hyperglycemia since liver oxidation of fatty acids provides energy for gluconeogenesis
other effects: hypertension, increased PAI-1 and less fibrinolysis, hyperuricemia, hyperandrogenism in women

Risk Factors – Family History – stronger hereditary component than type 1, possibly polygenic or mitochondrial

also obesity, sedentary life style, hypertension, aging, ethnicity (African, Hispanic, Asian, Native American)

the best prevention for type 1 diabetes is weight reduction

Impaired Glucose Tolerance (IGT) is the strongest risk factor

Histology – typically 60% of Islets are normal; amyloid infiltrate and surround Islets – represents peptide (amylin) packaged as fibrils in insulin granules that is co-secreted with C-peptide and insulin

Diagnosis – possible even when patient is asymptomatic – requires one of the following:

(1) High Fasting Plasma Glucose – at least 126mg/dl (7mM)

(2) Symptoms (polyuria, polysipsia) with a high random plasma glucose – 200mg/dl (11.1mM) or higher

Progression of the disease – measured by Oral Glucose Tolerance Test (OGTT)

measure plasma glucose 2 hours after 75 grams of glucose following an overnight fast

early disease – Impaired Fasting Glucose (IFG) – plasma glucose between 110 and 126 mg/dl

later disease – Impaired Glucose Tolerance (IGT) – plasma glucose between 140 and 200mg/dl

Insulin Resistance Syndrome (aka syndrome X; metabolic syndrome) – IGT along with an atherogenic lipid profile, HTN, abdominal obesity, insulin resistance, and hyperinsulinemia Þ 2-3x Ý risk for cardiovascular disease

Diabetes if >200 mg/dl

Complications of Diabetes Mellitus

Acute – hyperglycemia with ketoacidosis or non-ketotic hyperosmolar syndrome

Chronic – (1) glycation of tissue proteins and other macromolecules and (2) excess production of polyol compounds from glucose (i.e. Sorbitol via aldose reductase) lead to:

Retinopathy – loss of vision

Nephropathy – renal failure

Peripheral neuropathy – Ý risk of foot ulcers, amputation, and insensate Charcot joints

Autonomic neuropathy – GI, genitourinary, Cardiovascular symptoms

Sexual dysfunction

Increased Risk of Cardiovascular Disease (perhaps greatest public health problem in U.S.):

Microvascular complications – dysfunction of capillaries and arterioles in retina, renal glomeruli, large nerves
Macrovascular complicatoins – atherosclerosis of coronary, cerebral, or peripheral arteries
Hypertension
Abnormalities in lipoprotein metabolism
Periodontal disease

Category	Type I Diabetes Mellitus	Type II Diabetes Mellitus
Age of onset	<30	>30
Family History	Absent (slight genetic component)	Present
Cause	Insulin deficiency and b cell destruction	Insulin Resistance and b cell dysfunction
Insulin Treatment	Essential	Sometimes Required (for symptoms)
Microvascular complications (retinopathy, neuropathy)	Yes	Yes
Cardiovascular complications	Yes	Yes (especially)
Ketosis	spontaneous	From surgical stress
Epidemiology	10% of all diabetic patients	90% of patients