Diabetes mellitus type 1 mechanism
• 5–10% of all diabetes cases, 11–22 million worldwide • occur at any age • the symptoms occur after more than 90% of the β cells have been destroyed
Autoimmune destruction of the β-cells involving an expansion of autoreactive • CD4+ T helper cells (TH1, destruction by cytokines: IFN-γ, TNF etc.) • CD8+ T cells (killing directly) • Autoantibody-producing B cells (targets of autoantigens may include insulin, the β-cell enzyme glutamic acid decarboxylase (GAD), and islet cell autoantigen 512 (ICA512))
Diabetes mellitus type 2 mechanism
symptoms
• Hyperglycemia • Glycosuria, Polyuria (caused by osmotic diuresis secondary to hyperglycemia, which exceeds renal threshold for reabsorption), severe nocturnal enuresis (secondary to polyuria in young children)
• Polydipsia (due to the previous one) • Polyphagia (the catabolic state of insulin deficiency tends to a negative energy balance, which in turn leads to increasing appetite)
the classic triad of the onset
• Weight loss (over time, because of catabolic state)
Complex disease that involves an interplay of genetic and environmental factors and a proinflammatory state. There is • Insufficient insulin production from beta cells in the setting of • Insulin resistance (primarily within the muscles, liver, and fat tissue)
along with
Genetic susceptibility Environmental factors • HLA genes • Viral infections DR3 or DR4 haplotypes Coxsackie virus family, (95% in Caucasians), Rubella virus DR3/DR4 heterozygotes (40% of patients), DR3 or DR4 haplotypes concurrently with DQ8 haplotype (higher risk in siblings) • Non-HLA genes VNTRs in the promoter region of insulin, Polymorphisms in CTLA4 and PTPN22, AIRE mutations
• Nausea • Fatigue (caused by muscle wasting from the catabolic state, hypovolemia and hypokalemia), muscle cramps may be observed (caused by electrolyte imbalance)
• Blurred vision (results from the effect of the hyperosmolar state on the lens and vitreous humor)
complications Acute • Diabetic ketoacidosis (The lack of insulin and corresponding elevation of glucagon leads to the release of free fatty acids from adipose tissue (lipolysis), which are converted in the liver into ketone bodies (acetoacetate and β-hydroxybutyrate). β-Hydroxybutyrate can serve as an energy source in the absence of insulin-mediated glucose delivery, and is a protective mechanism in case of starvation. The ketone bodies, however, have a low pKa and therefore turn the blood acidic)
• Nonketotic hyperosmolar coma (hyperosmolar hyperglycemic state caused by severe dehydration and increased in osmolarity)
Insulitis in type 1 DM
Islets of Langerhans (endocrine pancreas) • α-cells (glucagon) • β-cells (insulin and amylin) • δ-cells (somatostatin) • PP (γ)-cells (pancreatic polypeptide) • ε-cells (ghrelin)
Chronic • Ophthalmologic complications • Diabetic nephropathy • Diabetic neuropathy • Macro- and microangipathies • Infections, gangrene (see: The complications common to both types of DM) Of treatment • Hypoglycemia (caused by too much or incorrectly timed insulin, too much or incorrectly timed exercise or not enough food)
• Lypohypertrophy (caused by insulin therapy, repeated insulin injections at the same site, it is an accumulation of extra subcutaneous fat due to topical anabolic effect of insulin, and may be unsightly, mildly painful)
References:
The universal blue circle symbol for diabetes International Diabetes Federation, 2006
world diabetes day 14 November
Other potentially important mechanisms: • Increased breakdown of lipids within fat cells • Resistance to and lack of incretins: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide) - synthesized by K cells in the mucosa of the GI tract) • Inappropriate regulation of metabolism by the CNS symptoms: fatigue, nausea and vomiting, severe abdominal pain, a characteristic fruity odor, and deep, labored breathing, also known as Kussmaul breathing
• about 90% of cases, 200 million worldwide • occur typically older than 40 years • frequently obese Genetic factors • more than 30 loci including genes associated with insulin secretion Environmental Factors • obesity (visceral) • sedentary lifestyle Insulin resistance results in failures to inhibit: • gluconeogenesis • lipoprotein lipase in adipose tissue (circulating FFAs↑) • and failure of glucose uptake in muscles after meals
The complications common to both types of DM Cataract
Normal lens
• Ophthalmologic complications Diabetic cataracts - the enzyme aldose reductase catalyzes the reduction of glucose to
symptoms
Many people, however, have no symptoms during the first few years and are diagnosed on routine testing • The classic triad Polyuria, Polydipsia, Polyphagia normal vision
• Weight loss • Blurred vision • Fatigue
early cataract
advanced cataract
rarely
• Hyperosmolar hyperglycemic state
Diffuse and nodular diabetic glomerulosclerosis (PAS stain)
complications and other symptoms
Diabetic coma
(see: The complications common to both types of DM)
β-cell dysfunction caused by
• Lipotoxicity • Glucotoxicity • Incretin effect • Amyloid depositions • Genetic deffects
Amyloidosis of a pancreatic islet in type 2 DM
Obesity can adversely impact insulin sensitivity in numerous ways:
• Excess FFAs (intracellular fatty acid oxidation, DAG↑, insulin signaling attenuating, competition with glucose for substrate oxidation)
• Adipokines: Adiponectin↓, contributing to insulin resistance
• Inflammation: excess of FFAs within macrophages and β-cells activates the inflammosome and lead to secretion of IL-1β, which results to inflammatory state and insulin resistence
Robbins and Cotran Pathologic Basis of Diseases (9e, 2015)
Basic Medical Endocrinology H. Maurice Goodman (4e, 2009)
Histology Text and Atlas with Correlated Cell & Molecular Biology - Michael H. Ross (6e, 2011)
Greenspan's Basic and Clinical Endocrinology (9e, 2011)
WHO diabetes diagnostic criteria Fasting glucose ≥7.0 (≥126) mmol/l(mg/dl) Glucose tolerance test (2h) ≥11.1 (≥200) mmol/l(mg/dl) HbA1c ≥48 (≥6.5) mmol/mol(DCCT%)
sorbitol through the polyol pathway. In the lens, sorbitol is produced faster than it is converted to fructose by the enzyme sorbitol dehydrogenase, and the intracellular accumulation of sorbitol leads to osmotic changes resulting in hydropic lens fibers that degenerate, to the generation of free radicals, lens epithelial cells apoptosis, and also by glycation of lens proteins form diabetic cataracts. Diabetic retinopathy - is the principal ophthalmologic complication of DM. The 5 stages in the progression of DR: 1. Dilation of the retinal venules and formation of retinal capillary microaneurysms 2. Increased vascular permeability (macular edema) 3. Vascular occlusion and retinal ischemia Cystic pockets 4. Proliferation of new blood vessels of fluid in the on the surface of the retina (VEGF-induced) central part of the retina 5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous
• Diabetic nephropathy Optical coherence tomography, Kimmelstiel–Wilson syndrome, or nodular Fluorescein angiography diabetic glomerulosclerosis and intercapillary glomerulonephritis - the basic pathophysiology is glomerular hyperfiltration, which leads to intraglomerular hypertension. Progression from glomerular hyperfilteration leads to the stage of basement membrane thickening. This is followed by expansion of mesangium and finally by nodular sclerosis. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis, and is the most common cause of chronic kidney failure and end-stage kidney disease. • Diabetic neuropathy - is nerve damaging disorders, thought to result from diabetic microvascular injury involving vasa nervorum in addition to macrovascular conditions. Peripheral distal symmetrical polyneuropathy, predominantly sensory, results in the loss of peripheral sensation (the combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation - “diabetic foot”). Autonomic neuropathy (orthostatic hypotension, respiratory sinus arrhythmia etc.) Proximal painful motor neuropathy or lumbosacral radiculoplexus neuropathy and diabetic amyotrophy Cranial mononeuropathy (ie, cranial nerve III, IV, or VI) • Macroangiopathy and microangipathy Coronary artery disease (MI), Renal vascular insufficiency, Stroke, Diabetic myonecrosis, Peripheral vascular disease (intermittent claudication, diabetic foot) caused by atherosclerosis. Advanced glycosylation end products (AGEs) and insulin resistance lead to endothelial dysfunction and atherosclerosis. Diabetes is often accompanied by underlying conditions that favor the development of adverse cardiovascular events: hypertension, dyslipidemia (TAGs and LDL↑, HDL↓) and PAI-1↑. • Infections Respiratory (the reason is the impaired immune response) Urinary tract (as a result of bladder dysfunction) Foot ulcers (secondary acquired) and other infections
The poster was made by Hovhannes Karapetyan 3 year student, Faculty of General Medicine, YSMU for the Pathophysiology Department of his alma mater All rights reserved © 2015 rd