1QQ # 2 Name on top edge, back side of paper Answer on blank side of paper. 1.For the negative feedback loop for thermoregulation a)The hypothalmus is an afferent pathway b)Somatic nerves are the efferent pathway to sweat glands c)Skeletal muscle tone would be increased as a response to a drop in core body temperature d)Peripheral nerves are the afferent pathway that convey skin temperature information e)Cutaneous arterioles would dilate in response to a drop in core body temperature.

Add covers or clothing or enter sleeping bag Skin tempAnd Core body temp Detected by thermoreceptors in skin Activity in sensory nerves Hypothalamus Sympathetic nerves Relax smooth muscle in cutaneous arterioles Blood flow to skin Heat loss by conduction & radiation Somatic nerves Muscle tone Heat production Sweat Glands Sweat production Evaporative heat loss Core temp. Voluntary behaviors Remove covers Turn on fan, etc via Heat loss Cerebral cortex Conductive heat loss Radiative heat loss Convective heat loss Central thermoreceptors Skeletal Muscles Somatic nerves

Acclimatization & Feedforward Deviations from set point are minimized Learned (by experience) Anticipates changes of a physiological parameter Response begins before there is a change in the physiological variable Minimizes fluctuations

Explain “chills” at onset of a fever Explain “sweat” when a fever “breaks” How does Tylenol reduce a fever? To reach new, Higher set point If setpoint is suddenly reset to a higher temperature, then actual temperature is LESS THAN the new set point, so one feels “cold” and adds clothing, curls up, and shivers. These are “Chills.” If setpoint is reset to a lower temperature or back to normal, then actual temperature is GREATER THAN the new lower set point, so one feels “hot” and removes clothing, fans, and sweats. These are “the sweats” when a fever breaks. Central & Peripheral Thermoreceptors Tylenol and other non- steroidal anti- inflammatory drugs (NSAIDS) suppress the production of eicosanoids (IL-1, IL-6, etc) so effect of these on the set point in hypothalamus is minimized. p. 579 Fig 16-18

Failure of 1. Brain function & 2. Heat loss mechanisms Increase Body Temp. Increase cell metabolism Sympathetic outflow Blood Pressure Blood Flow to brain Disrupted function of neurons Cutaneous vasodilation Heat Stroke Sweating Blood volume Excessive Sweating Massive Cutaneous Vasodilation Treating Heat Stroke

Positive feedback Inherently unstable Examples of Positive Feedback in Physiology –Heat stroke –formation of blood clot –menstrual cycling of female sex hormone concentrations at ovulation –generation of action potentials in nerve fibers –uterine contractions during childbirth Each of these examples terminate naturally (self limiting) Homeostasis is achieved by negative feedback loops: the integrator detects deviations from set point and orchestrates responses produced by effectors that return the parameter toward the set point.

Plasma Glucose Homeostasis Glucose metabolism Hormonal Control Disruptions of glucose homeostasis A Case Study

Homeostasis of Plasma Glucose Concentration Normal physiological range: mg/dl What is the set point? Why is too much plasma glucose harmful? Plasma glucose concentration = glucose entering the plasma – glucose leaving the plasma What are the mechanisms that regulate plasma glucose concentration? What are the components of the negative feedback loop: –Glucose receptors? –Afferent pathway? –Integrator? –Efferent pathway(s)? –Effector organ(s)? Phases: absorptive, post-absorptive, and fasting

Graph your daily caloric intake over a 48 hour period 6am 6pm Noon MN Calories consumed 6am Noon Plasma Glucose ? ? Overlay absorptive and post-absorptive phases on the graph

Fig =sink Absorptive Phase Hepatic Portal System Lipoprotein Lipase Once inside, glucose is converted to something else, thereby maintaining a concentration gradient for facilitated diffusion of glucose into cells.

Islets of Langerhans Alpha cells secrete glucagon Beta cells secrete insulin Delta cells secrete somatostatin Route of blood Liver Typical vasculature: Artery-Arteriole-Capillary-Venule-Vein-Heart Hepatic portal system Artery-Arteriole-Capillary-Portal Vessel- Capillary-Venule-Vein-Heart

Fig Post-absorptive phase Glucose Sparing Special case: Muscle wasting of starvation Note: Nervous tissue can use glucose and ketones Special term: Glycogenolysis & Gluconeogenesis

Major Points Absorptive phase lasts ~ 4 hours, cells “burn” glucose. During absorptive phase, energy needs provided by recently digested food During absorptive phase, excess is converted to stored fuel During post-absorptive phase, energy need met by release of stored fuels, most cells “burn” fatty acids, nervous tissue uses glucose and ketones. Fasting defined as greater than 12 hours after previous meal (some say 24 hrs) Fasting for several days has little effect on plasma glucose levels

The Issues How do cells “know” which fuel to “burn?” How do cells “know” when to synthesize glycogen or lipids and when to break down glycogen or lipid? What is responsible for the transitions from the absorptive and post-absorptive states? How does glucose get into “sink” cells?

Fig Identify sensors, afferent pathway, integrator, efferent pathway, effectors How is insulin secretion affected if plasma glucose is lower than set point? Which cell types have insulin receptors?

Activates some enzymes, inactivates others: see next slide! GLUT-4 Peptide hormone Exercise (via an undescribed mechanism) increases the number of glucose transporters in muscle cell membrane Diabetes mellitus: T1DM =beta cells fail to produce adequate insulin (5%) T2DM = target cells “resistant” (less responsive) to insulin ↑ plasma glucose →↑insulin secretion→↑glucose uptake into cells →↓ plasma glucose

Stimulatory actions of insulin in green Inhibitory actions of insulin in dashed red

Absorptive Phase Post-Absorptive Phase

? The Integrator integrates multiple inputs Glucose uptake, Storage, Lipogenesis WHY? FF Thinking about food Factors that influence Insulin Secretion

Another hormone that regulates plasma glucose concentration Glucagon prevails during post- absorptive phase Transition from absorptive to post- absorptive phase?

Graph your daily caloric intake over a 48 hour period 6am 6pm Noon MN Calories consumed 6am Noon Plasma Glucose Overlay INSULIN SECRETION on the graph Overlay GLUCAGON SECRETION on the graph

Glucose-counterregulatory controls (oppose effects of insulin) Glucagon Epinephrine Cortisol (permissive effect) Growth hormone (permissive effect)

Fig EPI, yet another horomone in glucose homeostasis, effects opposite of Insulin Don’t fret about receptors, afferent pathway, and integrator for this feedback loop.

Who Cares?

A Case Study On our website at A Case Study of Glucose Homeostasis A 35 year old male presented with the following complaints: frequent severe headaches upon awakening at 4:30 am, blurred vision, and fatigue due to excessive stress at work. The patient complained of routine 16 hr workdays followed by a midnight snack of breakfast cereal. An OGTT was ordered and provided the following results: During the second hour of the OGTT, the patient exhibited anxiety, paleness, hunger, tremulousness, and cold sweat. No additional tests were ordered. The patient was instructed to replace the midnight snack of cereal with a protein-rich snack.

Oral Glucose Tolerance Test Overnight fast, no beverages other than water Fasting blood sample Ingest 75 grams glucose Blood samples every 0.5 hours for 3-5 hours Plot plasma glucose concentration over time Compare curves Sugar content of Red Bull?

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Stress, Emergency (fight or flight) Effect on Beta cells Effect on Alpha Cells

The Answer to the Problem? Rationale for substituting protein for carbohydrate midnight snack?