Medical Pharmacology Chapter 29:  Diabetes

• Late Complications of Diabetes

  • Circulatory Abnormalities

    • Atherosclerosis: more extensive and occurs earlier (accelerated course)

      • Lesions initiated by oxidized LDL

    • Increased platelet adhesiveness

    • Increase secretion of endothelin-1

      • Endothelin-1:  powerful vasoconstrictor; vascular smooth muscle mitogen

    • Decreased nitric oxide production:

      • Nitric oxide: vasodilator; anti-mitogenic in vascular smooth muscle

    • Diabetes: procoagulant state

      • Increased levels of tissue factor

      • Deficiency of tissue factor pathway inhibitor type 1

      • Factor VIII elevated

      • Impaired fibrolysis: (probably as a result of increased tPA inhibitor, type 1)

    •  Symptoms:

      • Intermittent claudication, gangrene, impotence (vascular)

      • Coronary artery disease; stroke:common

      • Silent myocardial infarction

  • Retinopathy

    • Diabetic Retinopathy

      This whole-mount of the retina shows numerous microaneurysms of small retinal vessels. Ó 1999 KUMC Pathology and the University of Kansas, used with permission. courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

    • Diabetic retinopathy: leading cause of blindness in the U.S.

    • Retinopathic lesions

      1. Simple (background)

      2. Proliferative

    • Progression

      • Increased capillary permeability

      • Retinal capillary occlusion (saccular and fusiform aneurysms)

    • Vascular lesions associated with:

      • Proliferation of lining endothelial cells

      • Pericyte loss around vessels

    • Proliferative retinopathy is associated with new vessel formation and scarring.

  • Diabetic Nephropathy

    • "Diabetic nephropathy , a common sequela of diabetes mellitus, is manifested as severe arteriolar nephrosclerosis, glomerulosclerosis, and acute or chronic pyelonephritis. Diabetic glomerulosclerosis is shown in this slide. This glomerulosclerosis causes proteinuria in 55% of juvenile onset and 30% of adult onset diabetics. It usually presents about 16 years after the onset of diabetes. Diabetic glomerulosclerosis is the result of thickening of the basement membrane of the glomerular capillaries and increased cellularity of the mesangium, along with an increase in the mesangial matrix. The depostion of basement membrane in the mesangial matrix may become so pronounced as to form large nodules of hyaline material and is referred to as Kimmelstiel-Wilson disease which is specific for diabetes mellitus. This specimen shows the Kimmelstiel-Wilson variant of glomerulosclerosis. Note the large hyaline mass in the upper left hand portion of the screen and a smaller one in the center of the specimen. " Image Source: The Urbana Atlas of Pathology,University of Illinois College of Medicine at Urbana-Champaign Legends by Patricia J. O'Morchoe, M.D. Images from material collected by Donald R. Thursh, M.D. Concept and Design by Allan H. Levy, M.D., with the assistance of Ms. Jill Conway.(used with permission)

    • Renal disease: leading cause of death and disability due to diabetes.

    • 50% of end-stage renal disease in United States: diabetic nephropathy

    • Complication rates:

      • 35% of IDDM patients

      • 15 to 60% of NIDDM patients (ethnic background dependent; highest -- Pima Indians;lowest- Europeans)

    • Two pathologic patterns

      • Diffuse (more common)

        • Widening of glomerular basement membrane

        • Menangial thickening

          • Renal Corpuscle (5a and 5b represent Mesangium)

            Komorniczak M Renal Corpuscle, http://en.wikipedia.org/wiki/File:Renal_corpuscle.svg "The mesagnium is the pink structure inside the glomerulus between the capillaries (5a) and extending outside the glomerulus (5b)." http://en.wikipedia.org/wiki/Mesangium

      • Nodular

        • Periodic acid-Schiff-positive material: deposited at glomerular tuft periphery

        • Hyalinization of afferent and efferent arterioles

        • deposition of albumin and other proteins in tubules and glomeruli

  • Diabetic Neuropathy

    •  

      Diabetic Retinopathy

      Donovan J Doctor explains Diabetic Retinopathy-Stages, Symptoms, Prevention and Treatment. 1/2023 https://www.youtube.com/watch?v=5V3GPFUzCCk https://www.youtube.com/@DoctorODonovan

    • Major cause of morbidity

    • Peripheral polyneuropathy presents most commonly.

      • Bilateral, characterized by:

        1. Numbness

        2. Paresthesias

        3. Severe hyperesthesias

        4. Pain (deep-seeded, severe)

    • Mononeuropathy is associated with:

      • Wrist drop

      • Foot drop

      • Paralysis of third, fourth or sixth cranial nerve

    • Radiculopathy

      • Sensory syndrome: pain distribution of one or more spinal nerves, usually in chest wall or abdomen

    • Autonomic neuropathy

      •  Significant target: gastrointestinal tract -- symptoms include:

        • Esophageal dysfunction

        • Delayed gastric emptying

        • Constipation or diarrhea

      •  Orthostatic hypotension

      •  Syncope

      •  Cardiopulmonary arrest; sudden death

      •  Bladder dysfunction (may require chronic catheter drainage)

      •  Impotence/retrograde ejaculation

    • Treatment

      • Pain:

        • Although opioids may be used (e.g. tramadol (Ultram) side effects make these agents problematic for long-term therapy.

          • Other options include:

            • Gabapentin, prgabalin and carbamazepine (from the anti-seizure medication class)

            • Amitriptyline, imipramine, desipramine and nortriptyline from the tricycylic antidepressant class.

  • Diabetic Foot Ulcers

    • Diabetic Foot Ulcers

      Moore J Creating the ideal microcosm for rapid incorporation of bioengineered alternative tissues using an advanced hydrogel impregnated gauze dressing:  a case series.  The Foot and Angle Online Journal 1(9):2. September 2008 http://en.wikipedia.org/wiki/File:Neuropathic_heel_ulcer_diabetic.jpg

    • Secondary to diabetic neuropathy is  abnormal pressure distribution

      • Vascular disease (decreased perfusion): augments ulcer development

    • Infection: common (multiple organisms)

      • Initial antibiotic treatment (until culture results are available):

        • ampicillin-sulbactam plus gentamycin or aztreonam

  • Autonomic Dysfunction and Diabetes Mellitus

    • Initial finding: often asymptomatic abnormal vagal function (reduced heart rate variation with deep breathing)

      • Loss of myelinated and non-myelinated small nerve fibers in splanchnic distribution, carotid sinus, and vagus nerve

    • Enteric neuropathy:

      • Disturbances and gut motility.

      • Nausea/vomiting.

      • Achlorhydria.

      • Bowel incontinence.

    • Other Symptoms:

      • Impotence

      • Urinary incontinence.

      • Pupillary abnormalities.

      • Postural hypotension.

      • Symptoms of hypoglycemia -- blunted or detectable because damage to sympathetic adrenal gland innervation prevents epinephrine release.

      • Autonomic dysfunction may lengthen Q-T interval, an effect which may be associated with sudden cardiac death.

Karam, J. H., Pancreatic Hormones and Antidiabetic Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 684-703

Foster, D. W., Diabetes Mellitus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2060-2080