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Insulin promotes peptidesynthesis; glucagon uses the amino acids for gluconeogenesis.Thus, amino acids contribute to the mobilization of glucose inthe fasted state.These factors produce a rapid increase in blood glucose levels.In addition, glucagon has effects on lipid metabolism byincreasing β-oxidation of fatty acids.In normal fasting between meals, there is a balance betweenglucagon mobilizing glucose and insulin replenishing cellularglucose. However, with prolonged fasting, the glucagon effectpredominates, and following depletion of glycogen stores,there are high rates of gluconeogenesis and fatty acid oxidation. The increased oxidation of fatty acids to acetyl coenzymeA (acetyl-CoA) produces ketone bodies (acetoacetate andhydroxybutyrate), which can contribute to the acid load of thebody (Chapter 20).CLINICAL CORRELATEDiabetes MellitusDiabetes mellitus is a disease of impaired insulin function, resulting in hyperglycemia.
There are two classifications of diabetes,which relate to their etiology. Type 1 diabetes (T1D) is whatused to be called juvenile diabetes or insulin-dependent diabetesmellitus (IDDM); type 2 diabetes (T2D) was known asadult-onset diabetes or non–insulin-dependent diabetes mellitus(NIDDM).T1D is caused by progressive destruction of the pancreatic β-cellsby autoimmune attack, eventually resulting in minimal release ofinsulin and hyperglycemia. The autoimmune (T-lymphocyte)destruction may be caused by viral infection, but the exact causesare not well understood. The onset of hyperglycemia occursrapidly and usually becomes evident before the person reaches 20years old. The lack of insulin creates two immediate problems: (1)the glucose cannot enter the cells efficiently, and (2) the lack ofglucose in adipose cells decreases fat synthesis and increases fatbreakdown, releasing fatty acids into the blood—they get oxidizedto ketone bodies by the liver and can result in ketoacidosis (seeChapter 20).
Treatment is to stabilize the acid–base balance andstart insulin injections. Careful monitoring of blood glucose levelsand insulin injections are needed throughout life.In contrast, T2D appears to be a form of insulin resistance, resulting from a reduction in the insulin receptors on target tissues.
Ifinsulin is not present (T1D), or the receptors are reduced (T2D),the GLUT4 receptors will not be increased at the target cells, andglucose will not efficiently enter the cells and will be elevated inthe blood. Although insulin resistance is hereditary, the downregulation of receptors is also exacerbated with obesity. There are345SomatostatinSomatostatin is secreted in response to all ingested nutrients,as well as glucagon, and is inhibited by insulin. Somatostatin’srole in the pancreas is to suppress insulin and glucagon secretion. The apparent disconnection between these actions suggests that somatostatin acts to modulate the secretion of themajor hormones.several ethnic groups that have strong genetic predisposition forT2D, including Mexican Americans, Native Americans in theSouthwest, and African Americans.
There is also a higher incidence of T2D in African American and Native American womenthan in men of the same ethnicity, suggesting a further role of sexhormones in the insulin resistance. Whether or not the personwith T2D is obese or lean, prior to an increase in basal bloodglucose levels, there is a loss of sensitivity to insulin so that the βcells secrete more insulin to maintain euglycemia. Thus, inresponse to an oral glucose load, the prediabetic person willdisplay up to twice the insulin secretion, and have secretionoccur over a prolonged period, compared with a nondiabeticperson.
As the diabetes becomes more pronounced (basal hyperglycemia), insulin secretion can decrease, further compoundingthe hyperglycemia. In cases where T2D is precipitated by obesity,reduction in weight and increased exercise can control thehyperglycemia.Symptoms of uncontrolled hyperglycemia include the following:■■■■polyuria, from the osmotic effect of glucose in the urinepolydipsia, to compensate for urinary fluid lossespolyphagia, because glucose cannot enter the tissues, so thetissues are “starved” and hunger is stimulatedmetabolic ketoacidosis (primarily in T1D)Long-term uncontrolled or poorly controlled diabetes can lead toor be associated with:■■■■■retinopathy and blindnessnephropathy and renal failurehypertensioncerebrovascular diseaseperipheral vascular pathology(Cont’d)346Endocrine PhysiologyCLINICAL CORRELATE—cont’d■Whereas treatment of T1D is primarily with insulin injection(along with diet and exercise), treatment of T2D includes:■■■diet and exercise, because exercise increases GLUT4 transporters in cell membranesinsulinsulfonylureas and meglitinides (taken orally), which increaseβ-cell insulin secretionthiazolidinediones, which increase the sensitivity of muscle andfat tissue to insulin and decrease glucose production in theliverNonproliferative retinopathy (early stage)MicroaneurysmsHemorrhagesCotton-wool spotsHard exudateNarrowed arteriolesProliferative retinopathy(late stage)Massive hemorrhageRetinitis proliferansDiabetic nephropathyHistologic view ofdiabetic glomerulosclerosisIschemic stroke due to in situ thrombosis,usually triggered by plaque rupture in thecarotid or cerebral arteryMyocardial infarctionand related heart diseaseaccount for 70% of themortality in peoplewith diabetesMyocardial infarctionAtheromatousaorta andbranchesDiabetes mellitus is the leading cause ofend-stage renal disease in the Western worldMicrovascular and Macrovascular Complications of Diabetes Vascular complications canoccur with either type 1 or type 2 diabetes and include retinopathy (which can lead to blindness), cardiovascular disease, cerebrovascular disease, and diabetic nephropathy.
These complications are responsiblefor the high morbidity in diabetes.347CHAPTER30Calcium-Regulating HormonesOVERVIEW OF CALCIUM HOMEOSTASISAs previously discussed in Sections 5 and 6, calcium and phosphate homeostasis are closely linked, primarily because oftheir roles in bone metabolism.
Although several hormonesregulate both minerals, this chapter will focus on calcium andits regulation. Plasma calcium concentrations are under tightcontrol, with regulatory systems keeping normal levels∼2.4 mEq/L (or 9.4 mg/dL) of ionized calcium. Calcium iscritical to a myriad of functions, including contraction ofcardiac, skeletal, and smooth muscle; bone mineralization;transmission of nerve impulses; and blood clotting. Thus,alterations in plasma levels (higher or lower) can cause severeconsequences (see Clinical Correlates).Bone remodeling is a constant process involving deposition and resorption of minerals from the exchangeablecalcium-phosphate mineral pool. In the bone, osteoblastspromote bone deposition. Osteoclasts are phagocytic cells thatpromote bone resorption (absorption of minerals out of boneand into the extracellular fluid).
The activity of these two celltypes are typically in balance, with bone deposition equalingbone resorption. The ability to continually remodel bone isimportant and contributes to increasing bone strength whenbones and muscles are stressed or exercised and keeping upwith bone development in growing children.
When this remodeling activity decreases, as seen in the elderly, brittle bones canresult.Main Areas of Calcium RegulationThe intestines, kidneys, and bone are integral to calciumhomeostasis:■■■In the GI tract: In an average diet, adults ingest ∼1000 mgof calcium daily. The intestines absorb one third of this,but because additional calcium is lost through salivaryand gastrointestinal (GI) secretions, there is only about100 to 200 mg of net calcium absorption into the blood.1,25-dihydroxycholecalciferol (the active form ofvitamin D) and parathyroid hormone (PTH) facilitateintestinal calcium absorption.In the bone: The majority of the body’s calcium (∼99%)is stored in the skeletal bone, with much of the unmineralized calcium in the osteoid, which is an extracellularpool that is available for transport into bone or plasma.Thus, calcium readily moves between bone and plasmaas part of homeostatic regulation.
To a great extent, dailyplasma calcium homeostasis is regulated through theeffect of PTH to stimulate bone resorption, which addscalcium to the plasma. In contrast, vitamin D stimulatesentry of calcium into the bone calcium pool, providingsubstrate for bone deposition.In the kidney: To maintain balance, because 100 to200 mg of calcium is absorbed daily, 100 to 200 mg mustbe excreted by the kidneys. This represents about 2% ofthe filtered load of calcium to the kidneys, so 98% of thecalcium is reabsorbed, in part because of stimulationby PTH.Factors That Alter PlasmaCalcium ConcentrationForty percent of plasma calcium is bound to calcium-bindingproteins, mainly albumin. About 10% is bound to otheranions (including bicarbonate, phosphate, and citrate), soonly 50% of the calcium is free (ionized) and biologicallyactive. The plasma provides the calcium reservoir for boneand tissue and is under tight control by calcium regulatoryhormones; vitamin D; PTH; and to some extent, calcitonin.Hormone-independent changes in plasma calcium concentration can be caused by:■■■Acid–base disorders: In acidosis, albumin will be usedto buffer excess H+ in exchange for Ca2+, which increasesfree Ca2+ in the plasma; conversely, in alkalosis, H+ willbe released from albumin in exchange for Ca2+, andplasma free Ca2+ will increase.Changes in plasma protein concentrations: Because40% of plasma calcium is bound to proteins, changes inplasma proteins relate directly to total calcium: Decreasesin protein will decrease total calcium, and increases inprotein will increase total plasma calcium.Changes in plasma anion concentrations: This is especially relevant with plasma phosphate levels.
If phosphate increases, the calcium-phosphate complexesincrease, reducing ionized calcium, and vice versa.Because of this relationship, the hormone PTH regulatesboth calcium and phosphate.348Endocrine PhysiologyCLINICAL CORRELATEEffects of Altered Plasma Calcium ConcentrationHypercalcemia is an increase in plasma calcium concentration,which can have profound effects to depress nervous system activity. A 30% rise in plasma calcium (to ∼12 mg/dL) will affect thenervous system, causing symptoms that can include increasedurination, constipation, and important neurologic complicationsresulting in hyporeflexia.
If plasma calcium continues to rise(above 15 to 17 mg/dL), coma and death can result.cells, resulting in numbness and tingling, as well as muscle twitching and tetany. Tetany can occur when plasma calcium falls about30% (to ∼6 mg/dL), and death can occur if levels fall to 4 mg/dL.Hypocalcemia can result from changes in regulatory hormones,as well as dietary calcium deficiency. The effects of inadequatecalcium intake are depicted in the illustration.Changes in plasma calcium can be manifested in disorders involving parathyroid hormone and vitamin D (see “Calcium-RelatedPathophysiology” Clinical Correlate).Conversely, hypocalcemia, or decreased plasma calcium, willcause hyperexcitability of sensory and motor nerve and muscle1.
Deficient oralCa2+ intakeVitamin D4. PTH productionincreased3. Parathyroidglands stimulatedby low serum Ca2+25(OH)D5a. Elevated PTHpromotes conversionof 25(OH)D to1,25(OH)2D by25(OH)D-1␣-OHaseSerum andextracellularfluidCa2+Pi8. 1,25(OH)2Dstimulates increasedabsorption of Ca2+and increasedabsorption of Pi2. Serum Ca2+transiently loweredCa2+Pi9.
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