Chapter 8: Pathophysiology and Treatment of Metabolic Disease

Chapter 8: Pathophysiology and
Treatment of Metabolic Disease
Copyright © 2014 American College of Sports Medicine

Criteria for the Diagnosis of Diabetes

Description of Normal Glucose Metabolism
and Type 1, Type 2, and Gestational
Diabetes
• Type 1 diabetes: immune mediated, characterized by
pancreatic ß-cell destruction  absolute insulin deficiency
– Blood markers of pancreatic destruction
– Accounts for only 5%–10% of all cases
– Ketoacidosis
– Strongly inherited; greatest prevalence in African
and Asian descent

Diabetes
• Type 2 diabetes: characterized by insulin resistance with
relative insulin deficiency
– Insulin resistance:  glucose disposal rate elicited by
a given insulin concentration
• Occurs in ~90%–95% of diabetes cases
• Most patients with Type 2 diabetes are obese
and/or have central obesity.
•  risk for the development of microvascular and
macrovascular complications

Diabetes
• Gestational diabetes mellitus (GDM): any degree of
carbohydrate intolerance of variable severity with onset or first
recognition during pregnancy
– Screening in pregnancy: risk factor analysis and possibly
an OGTT
– Risk factors: marked obesity, history of GDM or delivery of
a previous large-for-gestation-age infant, glycosuria,
polycystic ovary syndrome, and a strong family history of
diabetes
• High waist-to-hip ratio and African American and
Hispanic race
– History of GDM =  risk for the development of Type 2 DM
Development, Risk Factors, and
Comorbidities for Diabetes
• Obesity, particularly visceral fat accumulation
–  risk of Type 2 DM
–  inflammation   risk of atherosclerosis and microvascular
complications
• Physical activity level is associated with the development of Type
2 diabetes.
– Population-based prospective study: Men with low fitness
had 1.9×  risk of IGT and 3.7×  risk of Type 2 DM versus
men with high fitness.
• Results held true regardless of age, parental history of
DM, alcohol consumption, and smoking.
– 30%–50% risk  associated with a physically active versus
sedentary lifestyle
• Risk factors for DM
– Age  45 yr
– BMI  25 kg · m-2
– Habitual physical inactivity
– First-degree relative with diabetes
– High-risk ethnic population such as African American,
Latino, Native American, Asian American, Pacific
Islander
– Delivering a baby weighing >9 lb or diagnosis of GDM
– Polycystic ovary syndrome
• Risk factors for DM (continued)
– Hypertension (140/90 mm Hg)
– Low HDL cholesterol (<35 mg · dL-1)
– High triglyceride level (>250 mg · dL-1)
– Previous diagnosis of IGT or IFG
– History of vascular disease
– NIH (NHLBI)-defined risk factors: waist
circumference of 40 in in men or 35 in in women
with BMIs of 25–29.9 kg · m-2  risk; extremely 
risk at BMI 40 kg · m-2
• Comorbidities
– Insulin resistance affects all normal metabolic actions of
insulin: glucose transport, hexokinase activity, glycogen
synthesis, and glucose oxidation.
• Insulin receptors on skeletal muscle cells undergo
autophosphorylation on tyrosine residues.
•  metabolic effect of insulin: GLUT4 translocation,
glucose disposal, and  the activity of glycogen
synthase and hexokinase
•  glucose clearance from circulation by skeletal
muscle and adipose tissue
– Dyslipidemia and hypertension
Development and Risk Factors for Other
Metabolic Conditions
• Prothrombotic and proinflammatory states as part of the
metabolic syndrome
– Inflammation, intimal-medial wall thickness of the
carotid arteries, and coagulation markers
– NHANES III survey found  CRP,  fibrinogen
concentrations, and  white blood cell counts in those
with metabolic syndrome versus those without.
• Physically active versus sedentary WITH the
metabolic syndrome
• Lower levels of CRP, WBC counts, and fibrinogen
levels as well as other adipokines including serum
amyloid-A, interleukin-6, and tumor necrosis
factor- levels
• Agreement between various definitions of metabolic syndrome
– Of 1,500 patients with Type 2 DM, 78% fulfilled the ATP
III criteria and 81% met the WHO criteria.
– In Cardiovascular Health Study, there was an 80%
concordance.
– In 400 obese adults, prevalence of WHO > ATP III criteria
– In 2,800 participants (San Antonio Heart Study), 1/4 met
both WHO and ATP III criteria; an additional 1/4 of adults
met only one of the criteria.
• Both definitions were predictive of all-cause and
cardiovascular mortality.
• ATP III but not WHO criteria were predictive of coronary
or cerebrovascular events.

• Healthy men with the metabolic syndrome showed that low
cardiorespiratory fitness was a risk factor for premature mortality.
• Prevalence of the metabolic syndrome in women was highest in
those with the lowest cardiorespiratory fitness.
•  levels of cardiorespiratory fitness attenuates effect of the
metabolic syndrome on all-cause and cardiovascular disease
mortality
– Men who do 1–3 h · wk–1 of moderate-intensity leisure-time
physical activity are 60% more likely to have the metabolic
syndrome than those who do 3 h · wk–1.
– Young adult Caucasian and African American women who
were moderately active versus physically inactive had
significantly  risk of having three risk factors of the
metabolic syndrome.
Role of Exercise/Physical Activity and
Body Weight on Diabetes
• Control of blood glucose
FIGURE 8-1. Mechanisms by which exercise training may improve insulin action and the control of blood glucose. TNF-α, tumor necrosis factor- α;
GLUT4, glucose transporter 4; FFA, free fatty acid. (Reprinted with permission from Ivy JL, Zderic TW, Fogt DL. Prevention and treatment of non-
insulin-dependent diabetes mellitus. Exerc Sport Sci Rev. 1999;27:1–35.)
• Type 2 diabetes: Physical inactivity and insulin resistance are
related.
– Japanese migrants and Pima Indians
– UPenn Alumni study: 6% lower risk of DM per 500 kcal ·
wk–1 of self-reported leisure-time physical activity
– Physician Health Studies: DM risk ~35% less for females
who reported vigorous exercise ≥ once per week; men
who exercise vigorously ≥5 times per week had a 42%
reduction in the age-adjusted risk of DM compared with
those who exercised less than once per week.
– Nurses’ Health Study: walking ≥2.5 h · wk–1 associated
with a 25%  in DM over an 8-yr follow-up
– Women’s Health Study: walking 2–3 h · wk–1 = 34% less
likely to develop DM than no exercise
• Type 2 diabetes: Aerobic capacity and insulin resistance are related.
– Finnish men in the lowest quartile of cardiorespiratory fitness 4×
more likely to get DM than highest two quartiles.
– 6-yr longitudinal study: Low fitness had  risk of impaired
glucose and DM compared to high fitness.
– Clinical trials in high-risk populations with impaired glycemic
control
• Chinese men who  physical activity levels were 46% less
likely to develop DM than a control group over 6 yr.
• Finnish and U.S. Diabetes Prevention Studies: 60%  DM rate
in intense lifestyle intervention group that included regular
physical activity versus control over 3–4 yr

• Type 2 diabetes: intervention studies
– Supervised training regimens have positive effects on
insulin sensitivity and glucose homeostasis in
individuals with IGT and Type 2 DM
– Moderate-intensity exercise training  HbA1C about
0.74 percentage points versus control group
– High-intensity resistance training  HbA1C about
1.2% versus control group

• Type 1 diabetes
– Physical activity  CV mortality.
– During a 6-yr follow-up period, Type 1 DM in the lowest
quintile of reported baseline physical activity had a sixfold
and fourfold higher mortality rate in men and women,
respectively, versus highest quintile.
– Randomized controlled clinical trial in Type 1 DM showed
that 12–16 wk of aerobic exercise training at 60%–80%
VO2 peak produced favorable changes in lipid, lipoprotein,
and apolipoprotein levels.
– Exercise training studies fail to show an independent effect
on HbA1C in patients with Type 1 DM.
Pharmacologic and Medical Treatment of
Diabetes
• Type 2 diabetes: First-line therapy is intensive lifestyle
modification ( physical activity, heart healthy diet, weight loss).
– Long-term compliance is challenging: UKPDS indicated that
only 25% of patients maintained optimal HbA1C (<7%) after
9 yr without an oral agent or insulin.
• Five groups of oral antidiabetic drugs:
1.  insulin secretion (insulin secretagogues)
2. Enhance the activity of other insulin secretagogues
3. Delay the rate of carbohydrate digestion and absorption (α-
glucosidase inhibitors)
4. Affect signaling pathways of hepatic gluconegenesis
5. Direct effects on insulin-responsive tissue (insulin sensitizers)
Diabetes
• Secretagogues (sulfonylureas and glinides)
–  circulating blood glucose by enhancing pancreatic
insulin secretion
– Effectiveness is highly dependent on adequate β-cell
function.
– Fasting glucose levels  2–4 mmol · L-1 with a 1–2
percentage point  of HbA1C

Diabetes
• α-Glucosidase inhibitors (acarbose, miglitol, and
voglibose)
–  digestion rate of carbohydrates in the proximal
small intestine, primarily lowering postprandial
glucose concentrations as they inhibit intestinal α-
glucosidase enzymes
–  postprandial glucose by 1–4 mmol · L-1;  HbA1C
by 0.5–1.0 percentage points

Diabetes
• Dipeptidyl peptidase-4 (DPP-4) inhibitors

– Prolongs and enhances the activity of the insulin
secretagogue, incretin
• Glucagon-like peptide-1 (GLP-1)
• Gastric inhibitory pepetide (GIP)
– Improves FPG and postprandial glucose
– Low risk of hypoglycemia

Diabetes
• Insulin sensitizers
– Biguanide: metformin
• Therapy of choice for overweight and obese individuals
with Type 2 diabetes
• Presence of insulin is crucial for its effectiveness.
• Improves insulin action in skeletal muscle and hepatic
tissue
•  fasting glucose by 2–4 mmol · L-1;  HbA1C by 1–2
percentage points
– Thiazolidinediones: pioglitazone
•  insulin sensitivity via multiple actions on gene regulation
•  HbA1C by 0.5–1.5 percentage points
Diabetes
• Insulin: last line of treatment reserved for those patients
who fail to respond adequately to a combination of orals
agents
– Disease has progressed to severe β-cell failure.
– Injected into subcutaneous tissue via syringe at
rotating sites (abdomen, upper arm, thigh, buttocks)
– Rapid acting (peak action: 0.5–1.0 h), short acting
(peak action: 2–3 h), intermediate acting (peak
action: 4–10 h), or long acting (peak action:
sustained for 20–24 h)
– Mixed dose of different types of insulin yields best
glucose responses.
Diabetes
• Type 1 diabetes
– Long-term complications of the eyes, kidneys, and
peripheral and autonomic nervous system
– Associated with a 10-fold  in CVD compared with age-
matched nondiabetic individuals
– Diabetes Control and Complication Trial
– Treatment goal: to achieve glycemic control to as near
normal as possible without the possibility of
hypoglycemia

Chapter 8: Pathophysiology and Treatment of Metabolic Disease

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Chapter 8: Pathophysiology and Treatment of Metabolic Disease

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Available Formats

Chapter 8: Pathophysiology and

Treatment of Metabolic Disease

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

• Dipeptidyl peptidase-4 (DPP-4) inhibitors

Copyright © 2014 American College of Sports Medicine

Copyright © 2014 American College of Sports Medicine

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