Glucose Metabolism and Diabetes

Mariel Arvizu, MDReview session

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

Glucose Metabolic pathways• Glycolysis – oxidation produces ATP and pyruvate from Glu – enter

Krebs cycle (citric acid cycle)ATP produced = 8-10; glycolisis is anaerobic processATP in Krebs cycle = 25 this is aerobicTOTAL = 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

Glucose regulation

InsulinGlucagon

Other hormones in Glucose

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.

AmylinGlucagon-like peptide (GLP-1) Gastric inhibitory peptide (GIP)

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.

Epinephrine, cortisol, and growth hormone:

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

Classification of Diabetes

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

T2DM vs T1DM

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

Epidemiology DM IGenetic 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

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

Clinical presentation

• Classic new onset chronic polydipsia, polyuria, and weight loss with hyperglycemia and ketones (urine=ketonuria;blood=ketonemia)

• Diabetic ketoacidosis

• Silent (asymptomatic)

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

Diabetes ketoacidosis (DKA) in T1DM

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

economic status

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.

Physical exam?

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 %

Normal range Hb1AC

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

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/diabetes/pubs/factsheet11.htm. Accessed September 20, 2012.

Global Prevalence of Type 2 Diabetes in 2000 and estimated prevalence in 2030.

Pathophysiology

Usually accompanied by other: METABOLIC SYNDROME–Hypertension–High cholesterol: LDL HDLHyperinsulinemia effects:1.Increased circulating free- fatty acids2.Inflammatory cytokines from excess fat and oxidative factors

Insulin secretion in T2DM

• beta cells requires glucose transport into the cell

• Animal models suggest mediated by the glucose transporter 2 (GLUT-2).

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

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

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)

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