Glucose Metabolism and Diabetes

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Glucose Metabolism and Diabetes

• Mariel Arvizu, MD
• Review session

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Carbohydrate Metabolism

• Glucose most important
• Monosaccharide
• Oxidation 1 g Glu 4 kcal of energy
• Energy stored in the form of ATP
• Mytochondria aerobic respiration were Glu
  becomes carbon dioxide and water

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Glucose Metabolic pathways

• Glycolysis oxidation produces ATP and pyruvate
  from Glu enter Krebs cycle (citric acid cycle)
• ATP produced 8-10 glycolisis is anaerobic
  process
• ATP in Krebs cycle 25 this is aerobic
• TOTAL about 36 ATP
• Glycogenesis conversion of excess Glu to
  Glycogen
• Glycogenolysis breakdown of glycogen into Glu
  (opposite to glycogenesis)
• Gluconeogenesis de novo synthesis of glucose
  from e.g. amino acids main source in human body
  lactate, glycerol, alanine, glutamine
• Pentose-phosphate pathway hexoses into pentose
  and NADPH generation prevents oxidative damage
  in cells.
• Carbon fixation known as photosynthesis were
  CO2 is reduced to glucose

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Glucose regulation
Insulin Glucagon
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Other hormones in Glucose
Amylin Glucagon-like peptide (GLP-1) Gastric
inhibitory peptide (GIP)

• Amylin is released along with insulin from beta
  cells.
• It has much the same effect as GLP-1
• It decreases glucagon levels decrease glucose
  production in liver
• slows the rate at which food empties from your
  stomach
• and makes your brain feel that you have eaten a
  full and satisfying meal.
• The overall effect of these hormones is to reduce
  the production of sugar by the liver during a
  meal to prevent it from getting too high.

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Epinephrine, cortisol, and growth hormone

• Epinephrine - promotes glycogenolysis, also
  promotes the breakdown and release of fat
  nutrients that travel to the liver where they are
  converted into sugar and ketones.
• Cortisol makes fat and muscle cells resistant to
  the action of insulin, and enhances the
  production of glucose by the liver. Under normal
  circumstances, cortisol counterbalances the
  action of insulin. Under stress or if a synthetic
  cortisol is given as a medication (such as with
  prednisone therapy or cortisone injection),
  cortisol levels become elevated and you become
  insulin resistant. keep your blood sugar under
  control.
• Growth Hormone Like cortisol, growth hormone
  counterbalances the effect of insulin on muscle
  and fat cells. High levels of growth hormone
  cause resistance to the action of insulin.

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Diabetes mellitus (DM)

• High glucose levels due to pancreatic dysfunction
  and/or insulin resistance
• Insulin resistance(insensitivity) condition in
  which cells do not respond properly to insulin

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Classification of Diabetes
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Dm type 1 vs Dm type 2

• T1DM- characterized by insulin DEFICIENCY
• T2Dm characterized by insulin resistance with
  relative insulin deficiency
• Body habitus patients with T2DM are usually
  obese
• Age very important, children with T2DM usually
  after puberty
• Family history stronger in T1Dm approx 10 have
  a relative affected

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T2DM vs T1DM
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Type I Diabetes

•  Type 1 diabetes mellitus (T1DM), one of the most
  common chronic diseases in childhood
• 2/3 diagnosis of diabetes in 19 years
• 1/3 of diagnosis are in adults
•  destruction of the insulin-producing pancreatic
  beta cells

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Epidemiology DM I

• Genetic susceptibility  The lifetime risk of
  developing T1DM is significantly increased in
  close relatives of a patient with T1DM
• No family history 0.4 percent
• Offspring of an affected mother 1 to 4 percent
• Offspring of an affected father 3 to 8 percent
• Offspring with both parents affected reported
  as high as 30 percent
• Non-twin sibling of affected patient 3 to 6
  percent
• Dizygotic twin 8 percent
• Monozygotic twin 30 percent within 10 years of
  diagnosis of the first twin and 65 percent
  concordance by age 60 years

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Other risk factors

• Viral infections enterovirus infections
• Immunizations
• Diet cow's milk at an early age
• Higher socioeconomic status
• Obesity
• Vitamin D deficiency increases mortality rates
• Perinatal factors maternal age, history of
  preeclampsia, and neonatal jaundice.
• Low birth weight decreases the risk of developing
  T1DM

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Clinical presentation

• Classic new onset chronic polydipsia, polyuria,
  and weight loss with hyperglycemia and ketones
  (urineketonuriabloodketonemia)
• Diabetic ketoacidosis
• Silent (asymptomatic)

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Classic New Onset most common

• Polyuria occurs when Glu rises 180 mg/dL
  exceeding the renal threshold for glucose, which
  results in glycosuria diuretic osmosis
• Bed wetting (Nocturia)
• Day time incontinence (previously continent)
• Polydipsia increased serum osmolality from
  hyperglycemia.
• Weight loss due to hypovolemia and increased
  catabolism, because insulin deficiency impairs
  glucose use in skeletal muscle and increases fat
  and muscle breakdown

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Diabetes ketoacidosis (DKA) in T1DM

• 2nd most common presentation 30
• Fruity-smelling breath
• Drowsiness and lethargy
• 50 if children age lt 3 years old
• More likely to happen in lower socio-economic
  status

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Diagnosis criteria for DM I American Diabetes
Association (ADA criteria)

• Fasting plasma glucose 126 mg/dL (7 mmol/L) on
  more than one occasion. Fasting is defined as no
  caloric intake for at least eight hours.
• Random venous plasma glucose 200 mg/dL (11.1 mmol
  /L) in a patient with classic symptoms of
  hyperglycemia.
• Plasma glucose 200 mg/dL (11.1 mmol/L) measured
  two hours after a glucose load of
  1.75 g/kg (maximum dose of 75 g) in an oral
  glucose tolerance test (OGTT). Most children and
  adolescents are symptomatic and have plasma
  glucose concentrations well above
  200 mg/dL (11.1 mmol/L) thus, OGTT is seldom
  necessary to diagnose T1DM.
• Glycated hemoglobin (A1C) 6.5 percent (using an
  assay that is certified by the National
  Glycohemoglobin Standardization Program). This
  criterion is more useful to diagnosis of type 2
  diabetes mellitus (T2DM) in adults, and should be
  confirmed by hyperglycemia.

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Physical exam?
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Glycated hemoglobin (A1C)

• Type of Hb used to indirectly calculate the
  average plasma glucose concentration
• Once Hb becomes glycosilated it remains that way
• Half-life Hb 4 weeks 3 months
• Normal range 6.5

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Normal range Hb1AC
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Diabetes Type 2

• characterized by
• Hyperglycemia
• insulin resistance
• relative impairment in insulin secretion
•  prevalence rises with increasing degrees of
  obesity
• Genetic predisposition 39 have at least one
  parent
• Ethnicity 2-6 fold in African-American,
  Hispanics, Native Americans in the U.S.
• Understanding the pathogenesis of type 2 diabetes
  is complicated by several factors

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Prevalence of T2DM in the U.S. in 2010
CDC. National diabetes fact sheet national
estimates and general information on diabetes and
prediabetes in the United States, 2011. Atlanta,
GA US Department of Health and Human Services,
CDC 2011. Available at http//www.cdc.gov/diabete
s/pubs/factsheet11.htm. Accessed September 20,
2012.
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Global Prevalence of Type 2 Diabetes in 2000 and
estimated prevalence in 2030.
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Pathophysiology

• Usually accompanied by other METABOLIC SYNDROME
• Hypertension
• High cholesterol LDL HDL
• Hyperinsulinemia effects
• Increased circulating free- fatty acids
• Inflammatory cytokines from excess fat and
  oxidative factors

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Insulin secretion in T2DM

• beta cells requires glucose transport into the
  cell
• Animal models suggest mediated by the glucose
  transporter 2 (GLUT-2).

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Insulin resistance

• Best predictor of DM 2
• severe with increasing age and weight, thereby
  unmasking a concurrent defect in insulin
  secretion in susceptible subjects
• In normal-weight nondiabetic subjects at high
  risk for T2DM, both fasting and post-glucose
  hyperinsulinemia predict future weight gain,
  which in turn predisposes to hyperglycemia

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Genetic Susceptibility

• monozygotic twin pairs with one affected twin
  90 of unaffected twins eventually develop the
  disease 
• First-degree relatives of patients have impaired
  nonoxidative glucose metabolism (indicative of
  insulin resistance)
• beta cell dysfunction, as evidenced by decreases
  in insulin and amylin release in response to
  glucose stimulation

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Diagnosis criteria for DM 2

• classic symptoms of hyperglycemia (thirst,
  polyuria, weight loss, blurry vision)
• random blood glucose value of 200 mg/dL
•  Fasting plasma glucose (FPG) values
  126 mg/dL (7.0 mmol/L)
•  two-hour post oral glucose challenge values of
  200 mg/dL
• glycated hemoglobin (A1C) values 6.5 percent
  (48 mmol/mol)

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Criteria for T2Dm criteria

• WHO -  FPG 126 mg/dL (7.0 mmol/L) or a two-hour
  post glucose challenge value 200 mg/dL 
• ADA Same as previous slide but they add A1C