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Diabetes Mellitus

Diabetes Mellitus. Lecture 1. Introduction. Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

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Diabetes Mellitus

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  1. Diabetes Mellitus Lecture 1

  2. Introduction • Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. • Some patients may experience acute life-threatening hyperglycemic episodes, such as ketoacidosis or hyperosmolar coma. • Acute life-threatening hypoglycemic episodes may occur as a result of therapy.

  3. Introduction • As the disease progresses, patients are at increased risk for the development of specific complications, including: • Microvascular complications • Retinopathy leading to blindness, • Nephropathy leading to renal failure, • and neuropathy (nerve damage), • Macrovascular complication • Atherosclerosis • May result in stroke, gangrene, or coronary artery disease

  4. Introduction • The number of people with diabetes has increased dramatically worldwide. • In 2014:It was estimated that ~ 382 million people have diabetes, and • By 2035: this number is predicted to reach 592 million, 80% of whom will live in low- and middle-income countries.

  5. (175 m)

  6. Introduction • Acute and chronic complications make diabetes the fourth most common cause of death in the developed world. • Diabetes caused 5.1 million deaths in 2013. • Every six seconds a person dies from diabetes • Worldwide diabetes caused at least $612 billion in health expenditures. Global health expenditure due to diabetes (20-79 years)

  7. Classification ofDiabetes Mellitus

  8. I- Type 1 Diabetes Mellitus • Approximately 5% to 10% of all cases of DM. • Patients usually have abrupt onset of symptoms (eg, polyuria, polydipsia, rapid weight loss). • They have insulinopenia (a deficiency of insulin) caused by destruction of pancreatic islet β-cells. • Dependent on insulin to sustain life and prevent ketosis. • Most patients have antibodies that identify an autoimmune process. • Some have no evidence of autoimmunity and are classified as type 1 idiopathic. • The peak incidence occurs in childhood and adolescence. • ~ 75% acquire the disease before the age of 18, but onset in the remainder may occur at any age.

  9. II- Type 2 Diabetes Mellitus • Accounts for ~ 90% of all cases of diabetes. • Patients have minimal symptoms, are not prone to ketosis, and are not dependent on insulin to prevent ketonuria. • Insulin concentrations may be normal, decreased, or increased, and most people with this form of diabetes have impaired insulin action. • Obesity is commonly associated, and weight loss alone usually improves hyperglycemia in these persons.

  10. II- Type 2 Diabetes Mellitus • However, many individuals with T2DM may require dietary intervention, oral antihyperglycemic agents, or insulin to control hyperglycemia. • Most patients acquire the disease after age 40, but it may occur in younger people. • T2DM in children and adolescents is an emerging, significant problem. • Among children in Japan, T2DM is now more common than type 1.

  11. III- Specific Types of Diabetes Mellitus Due to Other Causes • This subclass includes uncommon patients in whom hyperglycemia is due to a specific underlying disorder, such as: • Genetic defects of β-cell function. • Maturity onset diabetes of the young (MODY) • Genetic defects in insulin action. • Eg. type A insulin resistance syndrome, are due to insulin receptor gene mutations • Diseases of the exocrine pancreas • eg. cystic fibrosis • Endocrinopathies • eg. Cushing syndrome, acromegaly, glucagonoma

  12. III- Specific Types of Diabetes Mellitus Due to Other Causes • Administration of hormones or drugs known to: • induce β-cell dysfunction • eg, Dilantin, pentamidine • or to impair insulin action • eg, glucocorticoids, thiazides, β-adrenergics • Infection • Other genetic conditions • eg, Down syndrome, Klinefelter syndrome, porphyria

  13. IV- Gestational Diabetes Mellitus (GDM) • This is defined as any degree of glucose intolerance (ie, hyperglycemia) with onset or first recognition during pregnancy. • Estimates of the frequency of abnormalglucose tolerance during pregnancy range from less than 1% to 28%, depending on the population studied and the diagnostic tests employed. • The prevalence of GDM is increasing, at least in part, due to the considerable increase in obesity.

  14. IV- Gestational Diabetes Mellitus (GDM) • Women with GDM are at significantly greater risk for the subsequent development of T2DM mellitus, which occurs in 15% to 60%. • The risk is particularly high in women who have: • marked hyperglycemia during or soon after pregnancy, • women who are obese, and • women whose GDM was diagnosed before 24 weeks’ gestation • At 6 to 12 weeks postpartum, all patients who had GDM should be evaluated for diabetes using nonpregnant OGTT criteria. • If diabetes is not present, patients should be reevaluated for diabetes at least every 3 years.

  15. Categories of Increased Risk for Diabetes • Impaired glucose tolerance (IGT): (1979) • People who have blood glucose concentrations above normal, but less than those required for a diagnosis of diabetes mellitus. • It was defined as a 2-hour postload plasma glucose following an OGTT of 140 to 199 mg/dL • To avoid an OGTT, the category of impaired fasting glucose (IFG) was added in 1997 by the ADA and by the WHO in 1999 • IFG is diagnosed by a fasting glucose value between those of normal and diabetic individuals—namely, between 100 & 125 mg/dL. • (Note that the WHO and a number of other diabetes organizations define the cutoff for IFG at 110 mg/mL)

  16. Categories of Increased Risk for Diabetes • In 2009, hemoglobin A1c (HbA1c) was added as a criterion to diagnose diabetes. • People with HbA1c values below the cutoff for diabetes—that is, 6.5% but above the reference interval are at high risk of developing diabetes. • Individuals with IFG and/or IGT and/or intermediate HbA1c (5.7% to 6.4%) have been referred to as having “prediabetes” because they are at high risk for progressing to diabetes.

  17. Hormones that Regulate Blood Glucose Concentration

  18. Hormones that Regulate Blood Glucose Concentration • Normal glucose disposal depends on: • The ability of the pancreas to secrete insulin. • The ability of insulin to promote uptake of glucose into peripheral tissue. • The ability of insulin to suppress hepatic glucose production. • The major insulin target organs are liver, skeletal muscle, and adipose tissue. • These organs exhibit some differences in their responses to insulin. • For example, the hormone stimulates glucose uptake through a specific glucose transporter—GLUT4—into muscle and fat cells but not into liver cells.

  19. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin • Human insulin (MW 5808 Da) consists of 51 amino acids in two chains (A and B) joined by two disulfide bridges, with a third disulfide bridge within the A chain. • The amino acid sequence of human insulin differs slightly from insulin of other species, but the carboxyl terminal region of the B chain (B23 to B26), which appears crucial for the biological actions of insulin, is highly conserved among species. B23 to B26

  20. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin • Insulin from most animals is immunologically and biologically similar to human insulin, and in the past, patients were treated with insulin purified from beef or pig pancreas. • The most commonly used forms now are recombinant human insulins. • Preproinsulin, a protein of about 100 amino acids (MW 12,000 Da), is formed by ribosomes in the rough endoplasmic reticulum of the pancreatic β-cells. • Preproinsulin is not detectable in the circulation under normal conditions because it is rapidly converted by cleaving enzymes to proinsulin (MW 9000 Da), an 86 amino acid polypeptide.

  21. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Synthesis • This is stored in secretory granules in the Golgi complex of the β-cells, where proteolytic cleavage to insulin and connecting peptide (C-peptide) occurs. • Cleavage of proinsulin is catalyzed by two Ca2+-regulated endopeptidases: prohormone convertases 1 and 2 (PC1 and PC2). • PC1 hydrolyzes the molecule on the C-terminal end of Arg-31 and Arg-32 (at the BC junction) to yield split-32, 33-proinsulin. • PC2 cleaves proinsulin on the C-terminal side of dibasic residues Lys-64 and Arg-65 (at the AC junction) togenerate split-65,66-proinsulin. • Each enzymatic hydrolysis reaction is rapidly followed by the removal of two newly exposed C-terminal basic amino acids by carboxypeptidase-H to produce insulin and C-peptide.

  22. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Synthesis Processing of proinsulin. The enzymes prohormone convertase 1 and 2 (PC1 and PC2) act on proinsulin to form the appropriate split proinsulins. Carboxypeptidase-H (CPH) removes the two exposed basic amino acid residues (circles).

  23. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Synthesis • Less than 10% of proinsulin is metabolized via des-64-65-proinsulin, which is present in negligible amounts in humans. • Des-31,32-proinsulin is the major proinsulin conversion intermediate. • Glucose regulates biosynthesis of both proinsulin and PC1, but it has no effect on PC2 or carboxypeptidase-H. • At the cell membrane, insulin and C-peptide are released into the portal circulation in equimolar amounts. • In addition, small amounts of proinsulin and intermediate cleavage forms enter the circulation

  24. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Release • Glucose is the most important physiological secretagogue for insulin. • An increase in blood glucose concentrationstimulates insulin secretion within minutes. • Insulin release is potentiated by substances such as the incretin hormonesglucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as cholecystokinin, peptide YY, and oxyntomodulin, released from the gut in response to food. • Insulin release is inhibited by: • hypoglycemia, somatostatin (produced in the pancreatic δ-cells), • and various drugs • (eg, α-adrenergic agonists, β-adrenergic blockers, diazoxide, phenytoin, phenothiazines, nicotinic acid).

  25. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Release • In healthy individuals, insulin is secreted in a pulsatile fashion, with glucose and insulin the main signals in the feedback loop. • Glucose elicits the release of insulin from thepancreas in two phases. • The first phase begins 1 to 2 minutes after intravenous injection of glucose and ends within 10 minutes. • Sharp spike represents the rapid release of stored insulin. • The second phase, beginning at the point where the first phase ends, depends on continuing insulin synthesis and release and lasts until normoglycemia has been restored, usually within 60 to 120 minutes.

  26. Response of plasma insulin to glucose stimulation. A 20-g glucose pulse is given intravenously at time 0. A, Healthy subjects. B, Patients with T2DM mellitus. C, Patients with T1DM mellitus. Values before time 0 represent baseline. IRI, Immunoreactive insulin.

  27. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Release • With progressive failure of β-cell function, the first-phase insulin response to glucose is lost, but other stimuli such as glucagon or amino acids may be able to elicit this response. • Although the second-phase insulin response ispreserved in most patients with T2DM mellitus, both the first-phase response and normal pulsatile insulin secretion are lost. • In contrast, patients with T1DM mellitus exhibit minimal or no insulin response.

  28. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Degradation • On the first pass through the portal circulation, approximately 50% of the insulin is extracted by the liver, where it is degraded. • Additional insulin degradation occurs in the kidneys. • Insulin is filtered through the glomeruli,reabsorbed, and degraded in the proximal tubules. • The basal insulin secretory rate is about 1 U (43 µg)/h, with total daily secretion of about 40 U. • The half-life of insulin in the circulation is between 4 and 5 minutes.

  29. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Degradation • Proinsulin:Normally, only small amounts (about 3% of the amount of insulin, on a molar basis) of proinsulin enter the circulation. • However, the hepatic clearance rate for proinsulin is only 25% of that for insulin, and the half-life of proinsulin is approximately 30 minutes. • Therefore, in the fasting state, circulating proinsulin concentrations are approximately 10% to 15% of insulin concentrations.

  30. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Degradation C-Peptide:Proinsulin is cleaved to C-peptide and insulin. • C-peptide was initially thought to be devoid of biologicalactivity and was necessary only to ensure the correct structure of insulin. • More recent evidence reveals that C-peptide has biological activity, but its possible physiological significance remains controversial. • Although insulin and C-peptide are secreted into the portal circulation in equimolar amounts, fasting C-peptide concentrations are 5- to 10-fold higher than those of insulin owing to the longer half-life of C-peptide (approximately 35 minutes). • The liver does not extract C-peptide, which is removed from the circulation by the kidneys and degraded, with a fraction excreted unchanged in the urine.

  31. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Antibodies to Insulin • Antibodies to insulin develop in almost all patients who are treated with exogenous insulin. • These antibodies are usually present at low titer and produce no adverse effects. • On rare occasions (usually in insulin-treated patients with T2DM), high titers of insulin antibodies may cause insulin resistance. • There are several therapeutic approaches for treating these patients, and a quantitative estimate of the concentration of circulating insulin antibody does not appear to be of significant benefit. • Improvement in the purity of animal insulins and the widespread use of human insulin have reduced, but not totally eliminated, antibody production.

  32. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Antibodies to Insulin • The use of advanced insulin delivery systems—namely, continuous subcutaneous insulin infusion and inhaled insulin—has resulted in significantly increased concentrations of insulin antibodies. • Antibodies to insulin rarely develop in patients who have not received exogenous insulin. • There is no evidence to support the use of insulin antibody testing for routine care of patients with diabetes.

  33. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: Antibodies to Insulin • Although rare, patients with antibodies to the insulin receptor have been described. • On binding the receptor, these antibodies act as: • Antagonists, producing hyperglycemia (eg,in patients with acanthosis nigricans), or • Agonists, resulting in hypoglycemia.

  34. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: The Mechanism of Insulin Action • Although the metabolic effects produced by insulin are well known, the molecular mechanism of insulin action remains incompletely understood. • It is generally accepted that the initial event is the binding of insulin to specific receptors inthe plasma membrane. • The human insulin receptor, which is well characterized, is a heterotetramer, comprising two α- and two β-subunits. • The α-subunit is located on the outer surface of the plasma membrane and contains the site where insulin binds.

  35. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: The Mechanism of Insulin Action • The β-subunit extends intracellularly through the plasma membrane and contains an intrinsic tyrosine kinase. • Binding of insulin to the α-subunits induces a conformational change in the receptor, resulting in activation of the tyrosine kinase,which catalyzes the phosphorylation of tyrosine residues on several proteins. • One of the major substrates for this tyrosinekinase is the receptor itself, which is phosphorylated on multiple tyrosine residues

  36. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: The Mechanism of Insulin Action • The phosphorylated tyrosines on the target proteins act as docking sites for selected intracellular signal transducer proteins. • Proteins include those labeled phosphatidylinositol 3-kinase (PI3K) and growth factor receptor–bound protein 2 (Grb2), both of which mediate downstream signal transduction events. • Similar to other growth factors, insulin stimulates the mitogen-activated protein (MAP) kinase cascade via Ras. • In addition, PI3K activates Akt via 3-phosphoinositide dependent protein kinase-1 (PDK1).

  37. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin: The Mechanism of Insulin Action • The effects produced by insulin differ among tissues. • In skeletal muscle and adipose tissue, Akt regulates glucose transport by promoting translocation of GLUT4 (the insulin-sensitive glucose transporter) to the plasma membrane. • In the liver, Akt phosphorylates and inactivates GSK-3β (glycogen synthase kinase 3β), thereby enhancing glycogen synthesis. • Akt also suppresses gluconeogenesis and activates lipogenesis in the liver.

  38. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin:Glucose Transport • The transport of glucose into cells is modulated by two families of proteins. • The sodium-dependent glucose transporters (SGLTs) • use the electrochemical sodium gradient to transport glucose against its concentration gradient. • SGLTs promote the uptake of glucose and galactose from the lumen of the small bowel and their reabsorption from urine in the kidney. • Members of the second family of glucose carriers are called facilitative glucose transporters (GLUT), • a family of membrane proteins that are encoded by the SLC2 genes (Table).

  39. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin:Glucose Transport

  40. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin:Glucose Transport • These transporters are designated GLUT1 to GLUT14, based on the order in which they were identified. • Eleven have been shown to transport glucose. • Many also transport other hexoses, such as galactose, fructose, mannose, and xylose.

  41. HORMONES THAT REGULATE BLOOD GLUCOSE CONCENTRATIONInsulin:Glucose Transport • When circulating insulin concentrations are low, most of the GLUT4 is localized in intracellular compartments and is inactive. • After eating, the pancreas releases insulin,which stimulates the translocation of GLUT4 to the plasma membrane, thereby promoting glucose uptake into skeletal muscle and fat. • Insulin-stimulated glucose transport into skeletal muscle is defective in T2DM mellitus, but the mechanism has not been established.

  42. CLINICAL UTILITY OF MEASURING INSULIN,PROINSULIN, C-PEPTIDE, AND GLUCAGON

  43. CLINICAL UTILITY OF MEASURING INSULIN,PROINSULIN, C-PEPTIDE, AND GLUCAGON

  44. PATHOGENESIS OF TYPE 1 DIABETES MELLITUS • T1DM mellitus results from cellular-mediated autoimmune destruction of the insulin-secreting cells of pancreatic β-cells. • In the vast majority of patients, destruction is mediated by T cells. • This is termed type 1A or immune-mediated diabetes. • The α-, δ-, and other islet cells are preserved. • The islet cells have a chronic mononuclear cell infiltrate, called insulitis.

  45. PATHOGENESIS OF TYPE 1 DIABETES MELLITUS • The autoimmune process leading to T1DM begins months or years before the clinical presentation, and an 80% to 90% reduction in the volume of β-cells is required to induce symptomatic T1DM. • The rate of islet cell destruction is variable and is usually more rapid in children than in adults.

  46. PATHOGENESIS OF TYPE 1 DIABETES MELLITUSAntibodies • The most practical markers of β-cell autoimmunity are circulating antibodies, which have been detected in the serum years before the onset of hyperglycemia. • The best characterized islet autoantibodies are as follows: • Islet cell cytoplasmic antibodies (ICAs) • React with a sialoglycoconjugate antigen present in the cytoplasm of all endocrine cells of the pancreatic islets. • These antibodies are detected in the serum of 0.5% of normal subjects and 75% to 85% of patients with newly diagnosed T1DM.

  47. PATHOGENESIS OF TYPE 1 DIABETES MELLITUSAntibodies • Insulin autoantibodies (IAAs) • Present in more than 90% of children who develop T1DM before age 5, but in less than 40% of individuals who develop diabetes after age 12. • Their frequency in healthy people is similar to that of ICA. • Antibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) • have been found up to 10 years before the onset of clinical T1DM and are present in ~ 60% of patients with newly diagnosed T1DM. • GAD65 antibodies may be used to identify patients with apparent T2DM who will subsequently progress to T1DM.

  48. PATHOGENESIS OF TYPE 1 DIABETES MELLITUSAntibodies • Insulinoma-associated antigens (IA-2A and IA-2βA) • Directed against two tyrosine phosphatases, • have been detected in more than 50% of newly diagnosed T1DM patients. • Zinc transporter (ZnT8 ) • was identified in 2007 as a major autoantigen in T1DM. • ZnT8 is the least characterized of the autoantibodies in diabetes. • Initial analysis identified ZnT8 in 60% to 80% of patients with new-onset T1DM compared with less than 2%of controls and less than 3% of individuals with T2DM. • More important, antibodies to ZnT8 are detected in approximately 26% of patients with T1DM who are negative for other islet autoantibodies.

  49. PATHOGENESIS OF TYPE 1 DIABETES MELLITUSAntibodies • RIA, ELISA & new technique plasmonic chip-based assays

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