1. Chapter 10 Physical Activity and Diabetes “A MELTING OF THE FLESH AND LIMBS TO URINE.” ARETAEUS OF CAPPODOCIA, AD 150

2. P-244  (2005): 220 Million people suffer from diabetes mellitus worldwide—which may double by 2030.  This is from aging populations, unhealthy diets, obesity and a sedentary lifestyle.  In the USA diabetes is the leading cause of adult blindness, end-stage kidney failure, and nontraumatic amputations.  Diabetes is the 7 th leading cause of death in the USA and it increases the risk of CHD, hypertension and stroke 2— 4 x.  Diabetes Mellitus is a chronic disease caused by a deficiency in the production of insulin or in tis use to transport glucose from the blood into other tissues. The result is excess glucose in the blood, hyperglycemia, which is toxic.  The hallmark symptoms of diabetes are: Polyuria: excessive urination; Polydipsia: persistant thirst; Polyphasia: excessive hunger, and chronic fatigue or apathy.  Diabetes: Dia (Greek—”across”) and the Greek verb “bainen” (“to walk”) and a noun derived later meaning “siphon” was first used about 250 BC. The Latin word “Mellitus” means “sweetened with honey” was later added to describe the urine.

3.  About 150 AD Greek physicians wrote how diabetes “melted the flesh.” Greco-Roman physicians prescribed exercise to treat diabetes.  The US has the 3 rd highest # of cases (26 mill). That is more than half the cases in India (51 mill) and China (43 mill)—nations that each have about 4 x as many people.  Nearly 19 mill Americans have been told by a physician they have diabetes but another 7 mill have not been diagnosed. The # of people has increased 6 x in 1958 from 1.6 mill to 10 mill in 1997 and then nearly doubled to the current figure—a large portion of these people report being physically inactive.  If obesity and physical inactivity remain unchecked, it is predicted that diabetes prevalence in the US will increase to about 10% by 2030 and to 12%--about 48 mill by 2050.  Demographics: P-245

4. Clinical Features  There are 2 forms of diabetes: Type 1—IDDM or juvenile; Type 2—NIDDM.  Type 2 accounts for about 90% of all diabetes worldwide.  The focus of this chapter is Type 2 because it is highly preventable by diet, weight loss and activity.  Ketosis /k ɨˈ to ʊ s ɨ s/ is a state of elevated levels of ketone bodies in the body. [1] It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when liver glycogen stores are depleted. The ketone bodies acetoacetate and β-hydroxybutyrate are used for energy./k ɨˈ to ʊ s ɨ s/ketone bodies [1]ketogenesisglycogenacetoacetateβ-hydroxybutyrate  Type 2 diabetes results from the development of insensitivity of muscle and fat cells to insulin, leading to high blood glucose levels. Increased physical activity and weight loss can normalize blood glucose in 50% of cases.

5.  Normal blood glucose is 80-100 mg/dl postabsorptively (well after the last meal has been digested) and is normally elevated postprandially (after a meal).  In unregulated diabetics, blood glucose typically is about 300 to 400 but can be as high as 1000 mg/dl.  When glucose is over 180-200 there is sugar exudate (overflow) into urine.  HbA1c is a lab test that shows the average level of blood sugar (glucose) over the previous 3 months. It shows how well you are controlling your diabetes.  The American Diabetes Association advises patients with impaired glucose tolerance, impaired fasting glucose, or an HbA1c of 5.7% to 6.9% lose 5% to 10% of their body weight and increase their moderate physical activity by at least 150 min each week.

6. Health Burden of Diabetes  P-248  Chronic complications of uncontrolled diabetes include CHD, nerve diseases, blindness, kidney failure, and amputation of limbs. CVD is 2-4 X more common and risk of stroke is 2-4 x higher. 75% of people with diabetes have hypertension and 60%-70% have mild to severe diabetic nerve damage.  Diabetic neuropathy:  Diabetic retinopathy:  Loss of limbs:  Renal disease:  Complications in pregnancy:

7. Risk Factors  Diabetes is partly a hereditary disease. Excess body weight, insulin resistance, high BP, high cholesterol and gestational diabetes are modifiable.  Physical inactivity and weight gain are key modifiable risk factors.  Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids. Thus insulin not only promotes the use of glucose above fatty acids as the fuel of choice for energy production; it also contributes to the storage of fat in adipose tissue.  Neurons can only use glucose as fuel—adipose, muscle and liver cells can use fatty acids and protein as fuels when glucose is not available.  Glucagon

8. Etiology of Type 2 Diabetes  P-250  Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years. IGT is also a risk factor for mortality. [pre-diabetichyperglycemiainsulin resistancetype 2 diabetes mellitus  1—Insulin resistance leads to elevated glucose levels; 2—The liver increases glucose production; 3—The pancreas causes increased insulin secretion, then b-cell dysfunction; impaired glucose tolerance  Adipose cells have a key role in developing insulin resistance! (P-251, right column, second paragraph). Adipose tissue acs as an endocrine organ by secreting proteins such as leptin and adiponectin that act like hormones to modify the effects of insulin.  Leptin, which acts in the brain to influence satiety, also acts in the liver and skeletal muscle to help regulate the action of insulin. Deficiencies in leptin levels or signaling are linked with insulin resistance. Leptin replacement may improve blood glucose regulation.

9.  Glucostatic Medication for Type 2 Diabetes: P-252  How Does Exercise Improve Glucose Use? Increased use of fat as fuel and increased mitochondria in skeletal muscle could directly increase insulin sensitivity.  The contraction of skeletal muscle results in several metabolic events that increase glucose uptake without use of insulin. AMP-Activated Protein Kinase: 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate- activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells. [1]enzymesubunitsenzymeliverbrainskeletal musclehepaticketogenesisinhibitioncholesterollipogenesistriglyceridelipolysispancreaticbeta-cells [1] AMPK acts as a metabolic master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids and the biogenesis of glucose transporter 4 (GLUT4) and mitochondriametabolicintracellular glucoseβ-oxidationfatty acidsbiogenesisGLUT4mitochondria A recent JBC paper on mice at Johns Hopkins has shown that when the activity of brain AMPK was pharmacologically inhibited, the mice ate less and lost weightJBCmiceJohns Hopkins

10. Effects of Physical Activity on Diabetes Risk: The Evidence  Primary: reducing initial occurrence; Secondary: reversal; Tertiary: delay of medical complications.  Studies: P-255  Effects of Obesity Versus Physical Activity on Risk: P-259:  Strength of the Evidence: P-262  Biological Plausibility: The hallmark features of type 2 diabetes are impaired insulin sensitivity and insufficient insulin secretion. % events are key (1) a decrease in insulin receptor number (2) impaired chemical signaling for insulin (3) impaired transport of glucose transporters to the cell membrane (4) impaired glucose transporter function and (5) impaired enzyme action  High body fat decreases insulin sensitivity—therefore—improved insulin sensitivity can be explained by lowered fat mass among physically active people.

11.  Glucose Use During Exercise: Skeletal muscle is the main tissue that determines total-body glucose use—therefore—exercise training could alter the sensitivity of muscle cells to insulin.  Increased insulin sensitivity after exercise---after glucose transport is greatly enhanced.  Exercise also benefits glucose control by aiding glucose transport for use as fuel during muscle contraction and by enhancing insulin sensitivity when people are not exercising.

12. Chronic Effects of Exercise on Diabetes 1.Lowers circulating insulin 2.Improves glucose tolerance 3.Reduces insulin resistance 4.Increases number of insulin receptors in skeletal muscle in people with type 2 diabetes 5.Increases insulin-like effect of muscle contraction, increases GLUT4 transporter 6.Increases insulin sensitivity in people with type 2 diabetes

13.  About 80% of patients with type 2 diabetes are obese—which contributes to the development of the disease.  Summary: vigorous activity 3 or more times per week provides most of the independent benefits of glucose control. Additional benefits of improved insulin sensitivity with daily activity occur through fat weight loss. The effect of lowered glucose after acute exercise lasts about 48h so exercising every other day each week may be sufficient to help maintain normalized blood glucose levels.