DIABETES MELLITUSDiabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism. A defective or deficient insulin secretory response, which translates into impaired carbohydrate (glucose) use, is a characteristic feature of diabetes mellitus, as is the resulting hyperglycemiaDiabetes mellitus is a chronic disorder characterized by abnormalities in fuel metabolism, including glucose, lipids, and amino acids.Abnormalities in glucose tolerance are central in both the diagnosis of diabetes and classic complications of the disease. Because of associated abnormalities in lipid metabolism, people with diabetes are also prone to develop atherosclerosis, especially those with type 2 diabetes.

Classification of Diabetes Mellitus•1. Type 1 diabetes (-cell destruction, leads to absolute insulin deficiency)••••••Immune-mediated••••••Idiopathic•2. Type 2 diabetes (insulin resistance with relative insulin deficiency)•3. Genetic defects of -cell function••••••Maturity-onset diabetes of the young (MODY), caused by mutations in:•••••••Hepatocyte nuclear factor 4[HNF-4] (MODY1)•••••••Glucokinase (MODY2)•••••••Hepatocyte nuclear factor 1[HNF-1] (MODY3)•••••••Insulin promoter factor [IPF-1] (MODY4)•••••••Hepatocyte nuclear factor 1[HNF-1] (MODY5)•••••••Neurogenic differentiation factor 1 [Neuro D1] (MODY6)••••••Mitochondrial DNA mutations•4. Genetic defects in insulin processing or insulin action••••••Defects in proinsulin conversion••••••Insulin gene mutations••••••Insulin receptor mutations•5. Exocrine pancreatic defects••••••Chronic pancreatitis••••••Pancreatectomy••••••Neoplasia••••••Cystic fibrosis••••••Hemachromatosis••••••Fibrocalculous pancreatopathy•6. Endocrinopathies••••••Acromegaly••••••Cushing syndrome••••••Hyperthyroidism••••••Pheochromocytoma••••••Glucagonoma•7. Infections••••••Cytomegalovirus••••••Coxsackie virus B•8. Drugs••••••Glucocorticoids••••••Thyroid hormone••••••-interferon••••••Protease inhibitors••••••-adrenergic agonists••••••Thiazides••••••Nicotinic acid••••••Phenytoin•9. Genetic syndromes associated with diabetes••••••Down syndrome••••••Kleinfelter syndrome••••••Turner syndrome10. Gestational diabetes mellitus

In order to understand the pathogenesis of the two major diabetes types, first we will briefly review normal insulin secretion and the mechanism of insulin signaling, since these aspects are critical to understanding the pathogenesis of diabetes.

NORMAL INSULIN PHYSIOLOGY

Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal, muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on glucose.Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. Insulin promotes glucose uptake and utilization in tissues (discussed later). The skeletal muscle is the major insulin-responsive site for postprandial glucose utilization, and is critical for preventing hyperglycemia and maintaining glucose homeostasis.

Figure 24-27 Hormone production in pancreatic islet cells. Immunoperoxidase staining shows a dark reaction product for insulin in cells (A), glucagon in cells (B), and somatostatin in cells (C). D, Electron micrograph of a cell shows the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. E, Portions of an cell (left) and a cell (right) also exhibit granules, but with closely apportioned membranes. The -cell granule exhibits a dense, round center. (Electron micrographs courtesy of Dr. A. Like, University of Massachusetts Medical School, Worcester, MA.)

Figure 24-28 Insulin synthesis and secretion. Intracellular transport of glucose is mediated by GLUT-2, an insulin-independent glucose transporter in cells. Glucose undergoesoxidative metabolism in the cell to yield ATP. ATP inhibits an inward rectifying potassium channel receptor on the -cell surface; the receptor itself is a dimeric complex of thesulfonylurea receptor and a K+ -channel protein. Inhibition of this receptor leads to membrane depolarization, influx of Ca2+ ions, and release of stored insulin from cells.

Figure 24-29 Metabolic actions of insulin in striated muscle, adipose tissue, and liver.

Figure 24-30 Insulin action on a target cell. Insulin binds to the subunit of insulin receptor, leading to activation of the kinase activity in the -subunit, and sets in motion a phosphorylation (i.e., activation) cascade of multiple downstream target proteins. The mitogenic functions of insulin (and the related insulin-like growth factors) are mediated via the mitogen-activated protein kinase (MAP kinase) pathway. The metabolic actions of insulin are mediated primarily by activation of the phosphatidylinositol-3-kinase (PI-3K) pathway.The PI-3K-signaling pathway is responsible for a variety of effects on target cells, including translocation of GLUT-4 containing vesicles to the surface; increasing GLUT-4 density on the membrane and rate of glucose influx; promoting glycogen synthesis via activation of glycogen synthase; and promoting protein synthesis and lipogenesis, while inhibiting lipolysis. The PI-3K pathway also promotes cell survival and proliferation.

The types of diabetesType 1 diabetes mellitus - Due to beta-cell destruction leading to an absolute insulin deficiency. Beta-cell loss may be immune-mediated (90%) or idiopathic (10%). Depending on the rate of beta-cell destruction (rapidly in children and young adults, and more slowly in older adults), all

patients eventually require insulin for glucose control and survival. Patients are prone to ketoacidosis. Type 1 diabetes is caused by the autoimmune destruction of beta cells in approximately 90% of people and results in an absolute deficiency of insulin.Type 2 diabetes mellitus - Due to a combination of insulin resistance and relative insulin deficiency. Often associated with obesity or an increase in truncal (visceral) fat. Ketoacidosis is uncommon; may occur during periods of illness or stress. Hypertension and dyslipidemia are frequently associated. Generally does not require exogenous insulin early in course of the illness. Type 2 diabetes is the consequence of a combination of insulin resistance and progressive beta-cell failure.

DIAGNOSIS OF DIABETES

  Tests

Stage FPG*Casual Plasma Glucose OGTT§

Normal <100 mg/dL (5.5 mmol/L)†

  2-hour PG < 140 mg/dL

Prediabetes Impaired fasting glucose ≥ 100 and <126 mg/dL (7.0 mmol/L)

  Impaired glucose tolerance 2-hour PG ≥ 140 mg/dL (7.7 mmol/L) but <200 mg/dL (11.1 mmol/L)

Diabetes FPG ≥ 126 mg/dL (7.0 mmol/L)

≥200 mg/dL (11.1 mmol/L) plus symptoms‡

2-hour PG ≥ 200 mg/dL (11.1 mmol/L)

FPG = fasting plasma glucose; PG = plasma glucose; OGTT = oral glucose tolerance test.The classic symptoms of diabetes are polyuria, polydipsia, and unexplained weight loss.

Predisposition factors: Age > 45 years Overweight (body mass index [BMI] ≥ 25 kg/m2) Family history of diabetes (i.e., parents or siblings with diabetes) Member of a high-risk ethnic population (African American, Hispanic, Native American,

Asian American, and Pacific Islanders) History of gestational diabetes or delivery of infant weighing more than 9 lb Habitual physical inactivity History of hypertension or dyslipidemia (HDL ≤ 35 mg/dL or high triglycerides ≥ 250

mg/dL) Previously identified with either impaired fasting glucose or impaired glucose tolerance

(prediabetes)

Polycystic ovary syndrome History of vascular diseaseThe susceptibility for type 1 diabetes is associated with the genetic expression of certain proteins coded by the human leukocyte antigen (HLA) region of the major histocompatibility complex. These proteins are present on the surface of lymphocytes and macrophages and are considered essential for triggering the autoimmune destruction of the beta cells. Although all of the genetic markers (HLA and others) for type 1 diabetes are not known, future progress in this field will allow population screening for genetic susceptibility.Pathogenesis of type 1

diabetes:For type 1 diabetes, the primary pathogenic step is the activation of host T lymphocytes against specific antigens present in the patient's own beta cells. These activated T cells orchestrate a slow destruction of the beta cells via the recruitment of T and B lymphocytes, macrophages, and cytokines. Morphologic study of the pancreases of children who died at the onset of diabetes has shown an inflammatory infiltrate of mononuclear cells confined to the islets-called insulitis. The final result is the total destruction of the beta cells over a span of years. The finding of high-titer islet-cell antibodies (ICAs) in the serum of a child is highly predictive for progression to type 1 diabetes. Various antigens that are expressed by the beta cell have been implicated as the target for the autoimmune attack. Candidate antigens include insulin itself and a 64-kDa protein (now recognized as glutamic acid decarboxylase [GAD]). The triggering event for T-cell activation against these autoantigens is unknown but may involve the exposure to some environmental substance that is antigenically similar to the autoantigen. The T cells that are activated against this environmental antigen can then cross-react with the antigen on the beta cells-a process called molecular mimicry. Suspected environmental triggers for type 1 diabetes are viruses, toxins, and foods.Pathogenesis of type 2 diabetes:Type 1 diabetes is characterized by an absolute insulin deficiency; however, type 2 diabetes is characterized by both a defect in insulin action (insulin resistance) and a relative insulin deficiency. Insulin resistance generally precedes insulin deficiency by several years or decades in most models of type 2 diabetes although recent reports have suggested that a beta-cell defect may be the initiating trigger for both. Elevated levels of fasting or postglucose load insulin levels are the hallmark of insulin resistance. Several quantitative techniques may be used to assess insulin sensitivity or insulin resistance.

PATHOGENESIS. The pathogenesis of the two types is discussed separately, but first we briefly review normal insulin metabolism, since some aspects of insulin release and action are important in the consideration of pathogenesis.Normal Insulin Metabolism. The chemical structure, molecular biology, biosynthesis, and secretory pathways of insulin are now understood in elegant detail. The insulin gene is expressed in the beta cells of the pancreatic islets, where insulin is synthesized and stored in granules prior to secretion. Release from beta cells occurs as a biphasic process involving two pools of insulin. A rise in the blood glucose levels, for example, calls forth an immediate release of insulin, presumably that stored in the beta-cell granules. If the secretory stimulus persists, a delayed and protracted response follows, which involves active synthesis of insulin. The most important stimulus that triggers insulin release is glucose, which also initiates insulin synthesis. Other agents, including intestinal hormones and certain amino acids (leucine and arginine), as well as the sulfonylureas, stimulate insulin release but not synthesis.Insulin is a major anabolic hormone. It is necessary for (1) transmembrane transport of glucose and amino acids, (2) glycogen formation in the liver and skeletal muscles, (3) glucose conversion to triglycerides, (4) nucleic acid synthesis, and (5) protein synthesis. Its principal metabolic function is to increase the rate oj glucose transport into certain cells in the body. These are the striated muscle cells, including myocardial cells, fibroblasts, and fat cells, representing collectively about two thirds of the entire body weight.Insulin interacts with its target cells by first binding to the insulin receptor. Since the amount of insulin bound to the cells is affected by the availability of receptors, their number and function are important in regulating the action of insulin. Receptor-bound insulin triggers a number of intracellular responses, including activation or inhibition of insulin-sensitive enzymes in mitochondria, protein synthesis, and DNA synthesis. One of the important early effects of insulin involves translocation of glucose transport units (GLUTs) from the Golgi apparatus to the plasma membrane, thus facilitating cellular uptake of glucose. There are several different forms of GLUTs, which differ in their tissue distribution and affinity for glucose. There is increasing evidence that some forms of diabetes may be related to reduced expression and activity of these carrier proteins (p. 573).Pathogenesis of Type I Diabetes. This form of diabetes results from a severe, absolute lack of insulin caused by a reduction in the beta-cell mass. Type I diabetes (IDDM) usually develops in childhood, becoming manifest and severe at puberty. Patients depend on insulin for survival; hence the term insulin-dependent diabetes mellitus. Without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma.Three interlocking mechanisms are responsible for the islet cell destruction: genetic susceptibility, autoim-munity, and an environmental insult. A postulated sequence of events involving these three mechanisms is shown in Figure 17-1. It is thought that genetic susceptibility linked to specific alleles of the class II major histocompatibility complex predisposes certain persons to the development of autoimmunity against beta cells of the islets. The autoimmune reaction either develops spontaneously or, more likely, is triggered by an environmental agent (e.g., a virus or chemical) that causes an initial mild injury to the beta cells. The immune reaction directed against the altered beta cells then causes further beta-cell injury, and eventually, when most of the cells are destroyed, overt diabetes mellitus appears (Fig. 17-2). With this overview we can discuss each of the pathogenetic influences separately.METABOLIC DERANGEMENTS. Insulin is a major ana-

bolic hormone in the body and therefore derangementof insulin function affects not only glucose metabolismbut also fat and protein metabolism. Indeed, all path-ways of intermediary metabolism are disrupted to alesser or greater degree in patients with diabetes mel-litus.The most profound deficiency of insulin and there-fore the most severe metabolic derangements are usu-ally encountered in type I diabetes. The utilization ofglucose in muscle and adipose tissue is sharply dimin-ished or abolished. Concurrently there is stimulation ofglycogenolysis, which is normally inhibited by insulinand favored by glucagon. Fasting blood glucose mayreach levels many times greater than normal, andwhen the level of circulating glucose exceeds the renalthreshold, glycosuria ensues. The excessive glycosuriainduces an osmotic diuresis and thus polyuria, causinga profound loss of water and electrolytes (Na, K, Mg,P; Fig. 17-4). This obligatory water loss combinedwith the hyperosmolarity resulting from the increasedlevels of glucose in the blood tends to deplete intracel-lular water, as, for example, in the osmoreceptors ofthe thirst centers of the brain. In this manner, intensethirst (polydipsia) appears. Through poorly definedpathways, increased appetite (polyphagia) develops,thus completing the classic triad of diabetic findings—polyuria, polydipsia, and polyphagia. With a deficiencyof insulin, the scales swing from insulin-promotedanabolism to catabolism of proteins and fats. Proteoly-sis follows, and the glucogenic amino acids are re-moved by the liver and used as building blocks ingluconeogenesis, worsening the deranged carbohydratemetabolism.Two important acute metabolic complications ofdiabetes mellitus follow, diabetic ketoacidosis and non-ketotic hyperosmolar coma.Diabetic ketoacidosis occurs almost exclusively intype I diabetes and is the result of severe insulin deficiency coupled with absolute or relative increases ofglucagon (see Fig. 17-4). The insulin deficiency causesexcessive breakdown of adipose stores, resulting inincreased levels of free fatty acids. Oxidation of suchfree fatty acids within the liver through acetyl CoAproduces ketone bodies. Glucagon is the hormone thataccelerates such fatty acid oxidation. The rate at whichketone bodies are formed may exceed the rate at whichacetoacetic acid and b-hydroxybutyric acid can beutilized by muscles and other tissues, thus leading toketonemia and ketonuria. If the urinary excretion ofketones is compromised by dehydration, the plasmahydrogen ion concentration increases and systemicmetabolic ketoacidosis results.In type II diabetes, polyuria, polydipsia, and poly-phagia may accompany the fasting hyperglycemia, butketoacidosis is rare. Adults, particularly elderly diabet-ics, develop nonketotic hyperosmolar coma, a syn-drome engendered by the severe dehydration resultingfrom sustained hyperglycemic diuresis, which is cou-pled with the inability of these patients to drink water.The absence of ketoacidosis and its symptoms (nausea,vomiting, respiratory difficulties) delays the seeking of

medical attention in these patients until severe dehy-dration and coma occur.MORPHOLOGY. At death a diabetic may have manymorphologic changes suggestive of the diagnosis anda few virtually diagnostic findings, or there may be nolesions that might not also be found in age-matchednondiabetics. This variability is poorly understood, butthree factors are probably significant: (1) the duration ofthe disease, (2) the adquacy of metabolic control, and(3) genetic factors. The duration of diabetes stronglyuences the development of anatomic changes. Gen-erally, regardless of the type of diabetes, with diseaseof 10 to 15 years' duration patients develop dermal,renal, and retinal microangiopathy, as well as athero-sclerosis more severe than that found in age-matchedcontrols. Those with poor control of hyperglycemia areat greater risk, for reasons already discussed. Genesother than those responsible for the diabetic state alsocondition the likelihood of complications. The occurrenceof both diabetic nephropathy and retinopathy seems tobe related to the genetic background, because somepersons seem to be protected despite the long durationof their disease. Basement Membrane Thickening (BMT) and Microan-giopathy. Thickening of basement membrane is charac-teristic of diabetes mellitus. When it affects capillaries itis referred to as microangiopathy. This microvascularalteration is most evident in the capillaries of the skin,skeletal muscle, retina, renal glomeruli, and renal me-dulla. However, BMT is also seen in such nonvascularstructures as renal tubules, Bowman's capsule, periph-eral nerves, placenta, and possibly other sites. Thenormal basal lamina consists of a relatively uniform layerof extracellular material separating parenchymal or en-dothelial cells from the surrounding connective tissuestroma. In diabetes this single layer is widened andsometimes replaced by concentric layers of hyaline ma-terial composed predominantly of type IV collagen. Itshould be noted that despite the increase in the thick-ness of basement membranes, diabetic capillaries aremore leaky than normal to plasma proteins. Thischange may be responsible for the glomerular lesions,and possibly neuropathy. It should be noted that indis-tinguishable microangiopathy can be found in aged non-diabetic patients, but rarely to the extent seen in pa-tients with long-standing diabetes.Pancreas. Changes in the pancreas are inconstant andonly rarely of diagnostic value. Distinctive changes aremore commonly associated with type I diabetes thanwith type II diabetes. Indeed, the pancreas may appearvirtually normal in persons with type II diabetes unlessprecise quantitation of the islet cell mass is attempted.One or more of the following changes may be present:(1) Reduction in the size and number of islets is seenmost commonly in type I diabetes, particularly withrapidly progressive disease. Most of the islets are sosmall as to escape detection in routinely stained sec-tions. Subtle reduction in the islet cell mass can bedemonstrated in type II disease as well, but doing sorequires special morphometric studies. (2) Increase inthe number and size of islets is especially characteris-tic of nondiabetic newborns of diabetic mothers. Pre-sumably, fetal islets undergo hyperplasia in response tothe maternal hyperglycemia. (3) Beta-cell degranulationimplies depletion of stored insulin and is most commonlyseen in type I disease. (4) Amyloid replacement of islets appears as deposits of pink, amorphous materialbeginning in and around capillaries and between cells. Atadvanced stages the islets may be virtually obliterated(Fig. 17-5). This change is often seen in long-standingcases of type II diabetes. As mentioned earlier, theamyloid in this instance is composed of amylin fibrils

derived from the beta cells. Similar lesions may be foundin elderly nondiabetics. (5) Two types of leukocytic

infiltration are found in the islets, principally in type Idiabetes. The most common pattern is a heavy T-lym-phocyte infiltration within and about the islets (insulitis).This is seen early in the course of the disease andresults from an immune reaction. Eosinophilic infiltratesmay also be found, particularly in diabetic infants whofail to survive the immediate postnatal period.Vascular System. Diabetes exacts a heavy toll on thevascular system. Whatever the age at onset, in thecourse of 10 to 15 years of the disease most diabet-ics develop significant vascular abnormalities. Ves-sels of all sizes are affected, from the aorta down to thesmallest arterioles and capillaries.The aorta and large- and medium-sized arteries sufferfrom accelerated severe atherosclerosis. Except for itsgreater severity and earlier age of onset, atheroscle-rosis in diabetics is indistinguishable from that innondiabetics (p. 279).Myocardial infarction, caused by atherosclerosis ofthe coronary arteries, is the most common cause ofdeath in diabetics. Significantly, it is almost as commonin diabetic females as in diabetic males. In contrast,myocardial infarction is uncommon in nondiabetic fe-males of reproductive age (p. 308). Gangrene of the lower extremities, as a result of advanced vasculardisease, is about 100 times more common in diabeticsthan in the general population. The larger renal arteriesare also subject to severe atherosclerosis, but the mostdamaging effect of diabetes on the kidneys is exerted atthe level of the glomeruli and the microcirculation. Thisis the subject of a later discussion.The bases of accelerated atherosclerosis are not wellunderstood, and in all likelihood multiple factors areinvolved. About a third to a half of the patients haveelevated blood lipid levels, known to predispose toatherosclerosis, but the remainder also have an in-creased predisposition to atherosclerosis. Qualitativechanges in the lipoproteins brought about by excessive nonenzymatic glycosylation may affect their turnoverand tissue deposition. Low levels of high-density lipo-proteins (HDL) have been demonstrated in type II dia-betes. Since HDL is a "protective molecule" againstatherosclerosis (p. 279), this could contribute to in-creased susceptibility to atherosclerosis. Diabetics haveincreased platelet adhesiveness to the vessel wall, pos-sibly owing to increased thromboxane A2 synthesis andreduced prostacyclin. In addition to all these factors,diabetics tend to have an increased incidence of hyper-tension, which is a well-known risk factor for atheroscle-rosis (p. 280).Hyaline arteriolosclerosis, the vascular lesion asso-ciated with hypertension (p. 462), is both more prevalentand more severe in diabetics than in nondiabetics, but itis not specific for diabetes and may be seen in elderlynondiabetics without hypertension. It takes the form ofan amorphous, hyaline thickening of the wall of thearterioles, which causes narrowing of the lumen (Fig.17-6). Not surprisingly, in the diabetic it is related notonly to the duration of the disease but also to the levelof the blood pressure. The cause and nature of thisvascular change are still uncertain. Although at one timeit was attributed to hypertension, so common amongdiabetics, it can also be seen in diabetics who do nothave hypertension. The hyaline material consists ofplasma proteins and basement membrane material. It ispresumed that the plasma proteins penetrate into theabnormally permeable walls of the arterioles.Kidneys. The kidneys are prime targets of diabetes. Infact, renal failure is second only to myocardial infarctionas a cause of death from this disease. Four types oflesions, collectively termed "diabetic nephropathy,"are encountered: (1) glomerular lesions; (2) renal vas-cular lesions, principally arteriolosclerosis; (3)pyelo-nephritis, including necrotizing papillitis; and (4) gly-

cogen and fatty changes in the tubular epithelium.A variety of forms of glomerular involvement maybe present: capillary basement membrane thickening,diffuse glomerulosclerosis, nodular glomerulosclerosis(Kimmelstiel-Wilson lesion), "fibrin caps," and "capsulardrops." The last two are sometimes called exudativelesions. The sclerotic lesions of the glomeruli destroyrenal function and constitute potentially fatal forms ofdiabetic nephropathy, but the exudative lesions arelargely of diagnostic interest. Changes in the capillary basement membrane takethe form of thickening of the basement membranes ofthe glomerular capillaries throughout their entire lengthand are part and parcel of diabetic microangiopathy.Under the electron microscope, thickening of the glo-merular basement membrane can be detected within afew years of the onset of diabetes, sometimes withoutany associated change in renal function.Diffuse glomerulosclerosis is found in most patientswith disease of more than 10 years' duration. It consistsof a diffuse increase in mesangial matrix along withmesangial cell proliferation and is always associatedwith basement membrane thickening. These lesions al-most always begin in the vascular stalk and sometimesappear to be continuous with the hyaline arteriolosclero-sis in the afferent and efferent arterioles (Fig. 17-7).When the diffuse glomerulosclerosis becomesmarked, these patients manifest the nephrotic syn-drome (p. 444), characterized by proteinuria, hypoal-buminemia, and edema.Nodular glomerulosclerosis describes a glomerularlesion made distinctive by ball-like deposits of alaminated matrix within the mesangial core of thelobule (Fig. 17-8). These nodules tend to develop inthe periphery of the glomerulus, and since they arisewithin the mesangium they push the peripheral capillaryloops ahead of them. Often these patent loops createhaios about the nodule. This lesion has also been calledintercapillary glomerulosclerosis and Kimmelstiel-Wilsonlesion, after the pioneers who described it. Nodularglomerulosclerosis occurs irregularly throughout the kid-ney and affects random glomeruli, as well as randomlobules within a glomerulus. In advanced disease manynodules are present within a single glomerulus, andmost glomeruli become involved. Uninvolved glomeruliand lobules all show striking diffuse glomerulosclerosis.The deposits are PAS-positive and contain mucopoly-saccharides, lipids, and fibrils, as well as collagen fibers,as do the matrix deposits of diffuse glomerulosclerosis.Often they contain trapped mesangial cells.Nodular glomerulosclerosis is encountered in perhaps10 to 35% of diabetics and is a major cause of morbid-ity and mortality. Like diffuse glomerulosclerosis, theappearance is related to the duration of the disease butconditioned by the genetic background. Unlike the dif-fuse form, which may also be seen in association withold age and hypertension, the nodular form of glomer-ulosclerosis is, for all practical purposes, highly sug-gestive of diabetes.Progression of diabetic glomerulosclerosis and itsconstant companion, advanced arteriolosclerosis,usually leads to obliteration of the vascular channelsin the glomerulus and to serious, sometimes fatal,impairment of renal function. As a consequence ofglomerular sclerosis, the tubules suffer ischemia and arereplaced by interstitial fibrous tissue. Both the diffuseand the nodular forms of glomerulosclerosis induce sufficient ischemia to cause overall fine scarring of thekidneys, marked by a finely granular cortical surface.Exudative lesions take two forms. Glassy, homoge-neous, strongly eosinophilic deposits in the parietal layerof Bowman's capsule, called capsular drops, may hanginto the uriniferous space. Similar-looking deposits, fibrincaps, may develop over the outer surface of glomerularcapillary loops. Both the capsular drop and the fibrin capare attributed to excessive leakage of plasma proteinsfrom glomeruli that were severely injured by either dif-

fuse or nodular glomerulosclerosis. Neither of these twolesions causes any impairment in renal function.Renal atherosclerosis and arteriolosclerosis consti-tute on/y one part of the systematic involvement ofvessels in diabetics. The kidney is one of the mostfrequently and severely affected organs; however, thechanges in the arteries and arterioles are similar tothose found throughout the body. Hyaline arterioloscle-rosis affects not only the afferent but also the efferentarteriole. Such efferent arteriolosclerosis is rarely if everencountered in persons who do not have diabetes.Pyelonephritis is an acute or chronic inflammation ofthe kidneys that usually begins in the interstitial tissueand then spreads to affect the tubules—and, possibly,ultimately the glomeruli. Both the acute and chronicforms of this disease occur in nondiabetics as well as indiabetics; they are described more fully on page 453.These inflammatory disorders are more common in dia-betics than in the general population, and once affected,diabetics tend to have more severe involvement.One special pattern of acute pyelonephritis, necrotiz-ing papillitis, is much more prevalent in diabetics thanin nondiabetics. It is however, not limited to diabeticsbut is also seen with obstructions of the urinary tract aswell as with analgestic abuse. As the term implies,necrotizing papillitis is an acute necrosis of the renalpapillae (Fig. 17-9). Diabetics are particularly prone todevelop this lesion, owing to the combination of ische-mia resulting from microangiopathy and increased sus-ceptibility to bacterial infection. One or more papillaemay be involved, bilaterally or unilaterally. The infarctedpapilla may slough off and be excreted in the urine,permitting a clinical diagnosis by examination of theurinary sediment. In diabetics, bilateral necrosis of allpapillae is not uncommon. When many papillae areinvolved, papillary necrosis causes acute irreversiblerenal failure. This lesion is described more fully on page454.Tubular lesions are also encountered in diabetesmellitus. Perhaps the most striking is the deposition ofglycogen within the epithelial cells of the distal portionsof the proximal convoluted tubules (and sometimes inthe descending loop of Henle). This lesion is variouslytermed glycogen infiltration, glycogen nephrosis, or Ar-manni-Ebstein cells. The glycogen creates clearing ofthe cytoplasm of the affected cells. This condition isbelieved to be a reflection of severe hyperglycemia andglycosuria for a period of days of weeks prior to death.No tubular malfunction has been connected with thistubular change.Eyes. Visual impairment, sometimes even total blind-ness, is one of the more feared consequences of long-standing diabetes. This disease is presently the fourthleading cause of acquired blindness in the UnitedStates. The ocular involvement may take the form ofretinopathy, cataract formation, or glaucoma. Retinop-athy, the most common pattern, consists of a constella-tion of changes that together are considered by manyophthalmologists to the virtually diagnostic of the dis-ease. The lesion in the retina takes two forms—nonproliferative or background retinopathy and prolif-erative retinopathy. The former includes intraretinal orpreretinal hemorrhages, retinal exudates, edema, venousdilatations, and, most important, thickening of the retinalcapillaries (microangiopathy) and the development ofmicroaneurysms. The retinal exudates can be either"soft" (microinfarcts) or "hard" (deposits of plasmaproteins and lipids). The microaneurysms are discretesaccular dilatations of retinal choroidal capillaries thatappear through the ophthalmoscope as small red dots.The pathogenesis of retinal microaneurysms is multifac-torial. Selective loss of retinal capillary pericytes occursearly and is believed to be a consequence of changes inthe basement membrane. Dilatations tend to occur atfocal points of weakening, resulting from loss of peri-cytes. In addition, retinal edema resulting from excessive

capillary permeability might cause focal collapse, makingthe vessels vulnerable to aneurysmal dilatation.The so-called proliferative retinopathy is associatedwith neovascularization and fibrosis. This lesion can leadto serious consequences, including blindness, especiallywhen it involves the macula. Vitreous hemorrhages canresult from rupture of the newly formed capillaries. It isof interest that about half the patients with retinal mi-croaneurysms also have nodular glomerulosclerosis.Conversely, patients who have nodular glomerulo-sclerosis are almost certain to have retinal micro-aneurysms.Nervous System. The central and peripheral nervoussystems are not spared by diabetes. The most frequentpattern of involvement is a peripheral, symmetric neu ropathy of the lower extremities that affects both motorand sensory function but particularly the latter. Otherforms include: (i) autonomic neuropathy, producing dis-turbances in bowel and bladder function, and sometimessexual impotence, and (ii) diabetic mononeuropathy thatmay manifest as sudden foot drop, wrist drop, or iso-lated cranial nerve palsies. The neurologic changes maybe due to microangiopathy and increased permeability ofthe capillaries that supply the nerves as well as directaxonal damage caused by alterations in metabolismdiscussed earlier.The brain, along with the rest of the body, developswidespread microangiopathy. Such microcirculatory le-sions may lead to generalized neuronal degeneration.There is in addition some predisposition to cerebralvascular infarcts and brain hemorrhages, perhaps re-lated to the hypertension and atherosclerosis often seenin diabetics. Degenerative changes have also been ob-served in the spinal cord. None of the neurologic disor-ders, including the peripheral neuropathy, is specific

for this disease. Figure 24-31 Stages in the development of type 1 diabetes mellitus. The stages are listed from left to right, and hypothetical -cell mass is plotted against age. (From Eisenbarth GE:Type 1 diabetes: a chronic autoimmune disease. N Engl J Med 314:1360, 1986. Copyright © 1986, Massachusetts Medical Society. All rights reserved.)

Figure 24-33 Obesity and insulin resistance: the missing links? Adipocytes release a variety of factors (free fatty acids and adipokines) that may play a role in modulating insulin resistance in peripheral tissues (illustrated here is striated muscle). Excess free fatty acids (FFAs) and resistin are associated with insulin resistance; in contrast, adiponectin, whose levels are decreased in obesity, is an insulin-sensitizing adipokine. Leptin is also an insulin-sensitizing agent, but it acts via central receptors (in the hypothalamus). The peroxisome proliferator-activated receptor gamma (PPAR) is an adipocyte nuclear receptor that is activated by a class of insulin-sensitizing drugs called thiazolidinediones (TZDs). The mechanism of action of TZDs may eventually be mediated through modulation of adipokine and FFA levels that favor a state of insulin sensitivity.MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONSPathologic findings in the pancreas are variable and not necessarily dramatic. The important morphologic changes are related to the many late systemic complications of diabetes. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In individuals with tight control of diabetes, the onset might be delayed. In most patients, however, morphologic changes are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues. These pertinent clinical, genetic, and histopathologic features that distinguish type 1 and type 2 diabetes.In both forms, it is the long-term effects of diabetes, more than the acute metabolic complications, that are responsible for the overwhelming proportion of morbidity and mortality. In most instances, these complications appear approximately 15 to 20 years after the onset of hyperglycemia. Cardiovascular events such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality in long-standing diabetics. The impact of cardiovascular disease can be gauged from the fact that it accounts for up to 80% of deaths in type 2 diabetes; in fact, diabetics have a 3 to 7.5 times greater incidence of death from cardiovascular causes compared to the nondiabetic population[100] ( Fig. 24-41 ). The hallmark of cardiovascular disease is accelerated atherosclerosis of the large and medium-sized arteries (i.e., macrovascular disease). The pathogenesis of accelerated atherosclerosis involves multiple factors.

Figure 24-34 Long-term complications of diabetes.

Figure 24-35 A, Insulitis, shown here from a rat (BB) model of autoimmune diabetes, also seen in type 1 human diabetes. (Courtesy of Dr. Arthur Like, University of Massachusetts,Worchester, MA.)

B, Amyloidosis of a pancreatic islet in type 2 diabetes.Figure 24-36 Severe renal hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is evident. (Periodic acid-Schiff [PAS] stain; courtesy of M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health

Science Center at San Antonio, TX.) Figure 24-37 Renal cortex showing thickening of tubular basement membranes in a diabetic patient (PAS stain).

Figure 24-38 Electron micrograph of a renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space.(Courtesy of Dr. Michael Kashgarian, Department of Pathology, Yale University School of Medicine, New Haven, CT.)

Figure 24-39 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface (left) and markedthinning of the cortical tissue (right). Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst (far right).

Figure 24-40 Sequence of metabolic derangements leading to diabetic coma in type 1 diabetes mellitus. An absolute insulin deficiency leads to a catabolic state, eventuating in ketoacidosis and severe volume depletion. These cause sufficient central nervous system compromise to lead to coma and eventual death if left untreated.TABLE Type 1 Versus Type 2 Diabetes Mellitus (DM)

Type 1 DM Type 2 DM Clinical Onset: <20 years Onset: >30 years

Normal weight ObeseMarkedly decreased blood insulin Increased blood insulin (early);normal to

moderate decreased insulin (late)Anti-islet cell antibodies No anti-islet cell antibodiesKetoacidosis common Ketoacidosis rare; nonketotic hyperosmolar

comaGenetics 30–70% concordance in twins 50–90% concordance in twins

Linkage to MHC Class II HLA genes No HLA linkageLinkage to candidate diabetogenic genes (PPAR, calpain 10)

Pathogenesis Autoimmune destruction of -cells mediated by T cells and humoral mediators (TNF, IL-1, NO)

Insulin resistance in skeletal muscle, adipose tissue and liver

-cell dysfunction and relative insulin deficiency

Absolute insulin deficiencyIslet cells Insulitis early No insulitis

Marked atrophy and fibrosis Focal atrophy and amyloid deposition-cell depletion Mild -cell depletion

CLASSIFYING DIABETES MELLITUS AND RELATED CONDITIONS "Diabetes" literally means "siphon", because of the osmotic diuresis produced by the glycosuria. This was known all-too-well to Hippocrates, who may have named it. Diabetes mellitus (MELL-uh-tuss, please) is "a chronic disorder of carbohydrate, fat, and protein metabolism characterized in its fully expressed clinical form by an absolute or relative insulin deficiency, fasting hyperglycemia, glycosuria, and a striking tendency toward the development of atherosclerosis, microangiopathy, nephropathy, and neuropathy" (old Big Robbins). Diabetes is our commonest serious metabolic disease, affecting maybe 5% of the population. On the average, it takes 15 years off the patient's life (JAMA 285: 628, 2001) and accounts for a tremendous amount health care expenses. You will need to know the terminology (which is often not used correctly): Diabetes mellitus ("overt diabetes", "manifest diabetes", etc.): the patient has... signs and/or symptoms of diabetes plus any serum glucose of 200 mg/dL of more, or...

a serum glucose of 200 mg/dL or more at the 2-hour point of a glucose tolerance test, or...

elevated fasting blood sugar over 126 mg/dL on two occasions with the patient in his or her usual state of health.

The fasting criteria are down from 140 mg/dL (Am. Fam. Phys. 58: 1355, 1998). It identifies people at risk for health problems from hyperglycemia.

There's talk today about distinguishing "impaired fasting glucose" (IFG, i.e., 110-125 mg/dL) and "impaired glucose tolerance" (IGT, i.e., 121-179 mg/dL at the two-hour mark). See Arch. Int. Med. 161: 397, 2001.

Type I diabetes and Type II diabetes (below) are sometimes called "primary diabetes", since they seem to be genetic diseases in their own right.

Secondary diabetes is said to exist when the metabolic disturbances are the result of some other identifiable illness, injury, molecular abnormality, etc., etc.

Impaired glucose tolerance ("glucose intolerance", "subclinical diabetes", "asymptomatic diabetes", "chemical diabetes", "latent diabetes"): fasting blood sugar is normal, but a glucose tolerance test is abnormal. Current recommendations are NOT go looking for this: Am. J. Med. 105(1A): 15S, 1998.

Gestational diabetes mellitus: diabetes mellitus first appearing during pregnancy, and perhaps disappearing when the pregnancy ends.

"Previous Abnormality of Glucose Tolerance" ("prediabetes", "latent diabetes"): the patient once had measurable glucose intolerance (as, when she was pregnant), but is chemically normal now (but may be at risk for future diabetes mellitus, depending on the circumstances).

"Potential Abnormality of Glucose Tolerance" ("prediabetes"): the monozygotic twin of a type II diabetic, or (less justifiably) someone else with a strong family history.

Not diabetes: Glucose intolerance only under some obvious physiologic stress (myocardial infarction, pneumonia, severe burns, terror of venipuncture, etc.) Mostly an epinephrine effect; probably cortisol contributes as well.

The new system recommended by the WHO and the American Diabetes Association (Br. Med. J. 317: 359, 1998):

Type I: autoimmune and idiopathic situations in which beta cell function is extreme, and there is an absolute insulin lack;

Type II: defects in insulin secretion, and/or a relative lack of insulin, and/or insulin resistance;

Type III: damage to the whole pancreas (old pancreatitis, cystic fibrosis -- diabetes from CF is uncommon but happens J. Ped. 142: 97, 2003) and autosomal dominant genetic syndrome (I'm clueless as to why these are lumped together);

Type IV: Gestational diabetes

InsulitisType I diabetesWebPath photo

PRIMARY DIABETES TYPE I ("juvenile onset", "labile", "ketoacidosis-prone", "insulin-dependent"): 10% of diabetics.

One person in 300 in the U.S. gets this kind of diabetes (rates vary considerably from nation to nation; * rates are higher at higher latitudes).

Typical case: A child (average age twelve years, but we now know you can get the disease at any age) presents with polyuria, polydipsia, and polyphagia of relatively sudden onset. The child is found to have very high blood glucose levels causing osmotic diuresis.

Before the era of injectable insulin, diabetic ketoacidosis (DKA) and death followed in short order.

You remember the pathophysiology of ketoacidosis from your physiology course. Future clinicians: Ketoacids impart the familiar "rotten apples" sweetness to these patients' breath.

Today, the child looks forward to a period of fairly good health while taking injectable insulin, checking blood glucose several times a day with chemical strips and a reflectance meter.

After 10-15 years, unless control is good, the diabetic starts to suffer with infections, eye problems, peripheral neuropathy, gangrene of the lower extremities, kidney disease, stroke, and coronary atherosclerosis.

Historically, death usually came about forty years after onset as the result of a myocardial infarction. By this time, 50% of patients had lost their kidneys, and nearly as many were blind, stroked out, legless, and/or in chronic pain from neuropathy. A well-treated, compliant diabetic typically does better today.

The essential lesion in type I diabetes is a severe absolute lack of insulin.

* Only half of patients have any evidence of insulin production (measure C-peptide in serum).

Insulin deficiency and hyperglycemia explain the presentation but do not explain the later complications of the disease.

"Type I diabetes is a genetically programmed, chronic autoimmune disease" (NEJM 314: 1360, 1986, an early review; update Nature 351: 519, 1991), with the acute-symptomatic phase sometimes triggered by an acute viral illness.

In other words, the etiology is kind-of-complex.

Genetic factors:

Siblings of those with Type I diabetes are at increased risk (25x).

Identical twins of those with Type I diabetes have a 50% chance of eventually getting it also.

Type I diabetes is strongly associated with HLA-related antigens DR3 and DR4. (* If one has the misfortune to have both, it's even worse.... The former association with some HLA-B antigens was due to their linkage to DR3 and DR4; and currently, it appears that the also-linked DQ is the closest important site.)

* As is so common when the immune system attacks gland parenchyma, the beta cells of these patients express HLA class II histocompatibility antigens. No one knows whether this is cause or effect.

* The molecular defect that permits type I diabetes to occur seems to be homozygous absence of aspartic acid in position 57 of the HLA class II DQ chain (Nature 329: 599, 1987; Nature 333: 710, 1988), at least in the U.S. Update on HLA links: J. Clin. Endo. Metab. 89: 4037, 2004. The famous locus IDDM1, where certain polymorphisms give a risk for type I diabetes, is a component of the HLA system (Diabetes 50: 1200, 2001).

The gene IDDM2 ("implicated in diabetes melitus") is a complicated, highly variable tandem repeat adjacent to the real insulin gene. Two variants are strongly linked to type I diabetes (update Diabetes 53: 1884, 2004).

The animal model of autoimmune diabetes is the non-obese diabetic mouse, which gets that way because of genes at three (or more) loci (Nature 353: 260, 1991; J. Imm. 152: 204, 1994). Update J. Immuno. 169: 6617, 2002; to date; the exact reasons for the famous mouse's diabetes remain elusive.

* The BB (formerly BB/W) rat is a strain discovered in 1977. These rats have autoimmune insulitis, and the majority develop acute-onset type I diabetes. They helped us find the IDDM1 and IDDM2 loci (Acta. Diabet. 35: 109, 1998).

Autoimmune factors:

Several types of IgG anti-beta-cell antibodies occur. One or more is present in the vast majority of type I diabetics the acute phase (contrast 0.5% in healthy people). It is now quite clear that they are etiologic, and that they are usually present before age 2 in children destined to get type I diabetes (Ann. Int. Med. 140: 882, 2004).

Their specificities include anti- glutamic acid decarboxylase (Nature 347: 151, 1990; NEJM 322: 1555, 1990; Lancet 341: 1378 & 1383, 1993; diabetogenic epitope Lancet 343: 1607, 1994; true both of NOD mice and people: Nature 366: 69 & 72, 1993).

There is also cell-mediated immunity directed against beta cells in most patients who have been studied. Again, the autoantigen is glutamic acid decarboxylase. Update Nature 391: 177, 1998.

There was generally a dense lymphocytic infiltrate in the islets of patients dying in the acute phase (rare nowadays).

* Maybe 1 in 5 of these people ends up with another autoimmune glandular disease (autoimmune Addison's disease, Hasmimoto's autoimmune thyroiditis, Grave's disease of the thyroid). Likewise, plenty of people, with or without other autoantibodies, have anti-islet cell antibodies but never go on to develop autoimmune diabetes.

The claim from the early 1990's that cow's milk is the trigger for autoimmune diabetes flopped (JAMA 276: 609 & 647, 1996, NEJM 329: 1853, 1993, and J. Clin. Endo. 87: 3192, 2002).

* All the recent stuff is from obvious "independent thinkers" (ignoring what we know of immunology: Food & Chem. Tox. 42: 707, 2004) and studies that invited recall bias (Ann. Nutr. Metab. 47: 267, 2003).

* The non-obese diabetic mouse does get some protection from drinking mother's milk instead of cow's milk. The experimentalists speculat at length about how perhaps this is because mother's milk contains insulin and/or other peptides to which the gut lymphocytes need to become tolerant (Diabetes 48: 1501, 1999). But think -- the experiment requires taking the experimental mice away from their mothers. This must have many far-reaching effects beyond just the exposure to cow's milk.

A few groups are "curing" mice of type I diabetes using immune manipulation (Freund's adjuvants, etc., etc.) Update J. Clin. Inv. 108: 63, 2001.

Viral factors: Clinically, Type I diabetes often follows a viral illness.

Worth knowing: Kilham rat parvovirus infection produces type I autoimmune diabetes in diabetes-resistant rats (Diabetes 45: 557, 1996; J. Immuno. 165: 2866, 2000). This is now a robust finding (J. Imm. 173: 137, 2004).

* Retrovirus IDDMK(1,2)22 remains controversial as a cause of type I diabetes. Some folks don't find it at all (Diabetes 48: 209 &

219, 1999); others find soft data suggesting a link (J. Hum. Genet. 46: 712, 2001).

* A Coxsackie B4 virus from the pancreas of a patient dying shortly after the onset of the illness destroys the beta cells of NOD (non-obese diabetic) mice; it's now clear that the virus causes a chronic infection of these islands (J. Inf. Dis. 171: 1131, 1995). Since this article, Coxsackie CB4 has been found commonly as a recent infection in kids coming down with diabetes.

In the non-obese diabetic (NOD) mouse, there is a specific defect in a group of T-suppressor cells. * A possible ligand to enhance these cells in mice and humans: Nat. Med. 7: 1052, 2001.

The mechanism of Coxsackie B4 induction of diabetes now seems clear -- the NOD mouse has lots of autoreactive-but-unactivated T-cells, Coxsackie B4 produces a mild infection of the beta cells, and bystander T-cells are activated ("bystander activation"). Happens in mice and maybe in kids.

Overwhelming infections with mumps or cytomegalovirus also have been implicated in rare cases of "type I diabetes". The pancreas can be destroyed by congenital rubella.

* A huge search for the "insulitis virus" in humans using molecular probes found nothing: JAMA 257: 1145, 1987.

What does all this mean? In most cases of type I diabetes, it is hypothesized that a viral infection triggers autoimmune destruction of the beta cells in genetically-predisposed individuals.

However, in most of these children, there have been progressive abnormalities of glucose metabolism in these patients long before the onset of illness (Br. Med. J. 294: 5, 1987).

Some stress ("maybe the virus") apparently causes decompensation at the "time of onset". Following recovery from the first episode of ketoacidosis, the "honeymoon period" begins, when control is easy for several years. (* Patients continue to produce some of their own insulin -- i.e., there is C-peptide in their blood -- during the "honeymoon".)

PRIMARY DIABETES TYPE II ("adult onset", "stable", "ketosis-resistant", "non-insulin-dependent"): 90% of diabetics.

Typical case:

An overweight adult (most over age forty) is discovered on routine screening to have elevated fasting glucose or glycosuria.

In other cases, the diabetes is discovered during evaluation of impotence, pain, eye trouble, stroke, foot trouble, bad infection, or coronary disease.

Some patients have their diabetic predisposition unmasked by pregnancy. Such women get better after the pregnancy, but are at greater risk for eventually developing type II diabetes.

Before the era of injectable insulin, nothing much was done for type II diabetics, even if the disease was detected. The patients got complications and had shorter life spans.

Today, the adult looks forward to dieting, doing aerobic exercise, and possibly getting treated with insulin or "diabetes pills", probably getting an ACE inhibitor, and maybe a statin for lipid control. Complications will occur as in Type I diabetes, depending on how well the patient is able to manage the hyperglycemia. Death will probably be due to a myocardial infarct.

Type II diabetes is a polygenic disorder, with its expression modified by a person's exercise habits and amount of bodyfat.

Identical twins have nearly 100% concordance for Type II diabetes.

There are no good HLA associations or phenomena pointing to autoimmunity.

A subtype of Type II diabetes which can present in young people ("maturity-onset diabetes of the young," MODY) is an autosomal dominant with 90% penetrance, and several loci. See below.

MODY accounts for about 10% of diabetics in some communities, and less-severe alleles of the genes are of course implicated in common type II diabetes.

The defect is usually in the glucokinase gene (Nature 356: 721, 1992; mechanisms Lancet 340: 444, 1990; diagnosis Lancet 345: 1313, 1995; pathophysiology Diabetes 46: 204, 1997; this enzyme, as you remember, is the key link in the signalling system by which beta cells monitor blood glucose).

There are a few other MODY genes too, all in the insulin-release system (Proc. Nat. Acad. Sci. 94: 13209, 1997; Diabetes 47: 1459, 1998; Diabete 52: 872, 2003). Update on genes Diabetes 53: 1894, 2004.

A single major genetic defect at a type II diabetes locus, and/or several minor defects at several of the loci, seems to be the underlying cause of type II diabetes.

Why these usually do not declare themselves at birth remains a mystery. Perhaps all that would do so have been strongly selected-against.

The insulin resistance genes to date, and the percentage of type II diabetics with each (Nature 373: 384, 1995, also Am. J. Clin. Path. 105: 149, 1996):

1%... mitochondrial DNA syndromes (often goes with deafness; Ann. Int. Med. 134: 721, 2001; many others)

?%... the mitochondrial uncoupling proteins (Diabetes 47: 1528, 1998; Diabetes 53: 1905, 2004).

1%... glucokinase

1%... insulin itself

1%... insulin receptor (* the severe form is "leprechaunism", a progeria: Biochim. Biophys. Acta.1402: 86, 1998)

15%... insulin receptor substrate (it's very complicated: Diabetes 52: 1544, 2003)

1%... GLUT4, the glucose-through-the-membrane transporter

?%... adiponectin, released from adipocytes, causes liver and muscle to burn triglyceride and be more insulin-sensitive (Nat. Med. 7 887, 2001; Nat. Med. 10: 452 & 524, 2004).

?%... hepatocyte nuclear factor alpha (causes MODY3; risk for classic type II; Diabetes 53: 2122, 2004)

?%... ICAM-1 (Lancet 362: 1723, 2003)

?%... calpain 10 (J. Clin. Endo. Metab. 87: 2606, 2002)

?%... beta adrenergic receptors (gives the munchies / obesity and diabetes: NEJM 333: 382, 1995; Clin. Endo. 59: 476, 2003).

?%... leptin (must be rare in humans, though of course in mice it's famous)

?%... phosphoenolpyruvate carboxykinase (J. Clin. Endo. Metab. 89: 898, 2004.

?%... Sulfonylurea receptor (Lancet 361: 22, 2003).

?%... mitochondrial fat-burning systems (no gene yet; NEJM 350: 664, 2004);

Expect LOTS more to be discovered.

* The lipoatrophic diabetic mouse has zero bodyfat and extreme insulin resistance with diabetes. A gene product awaits discovery and characterization (Diabetes 51: 2113, 2002). This is supposed to be a

model for both a few human genetic syndromes and the lipoatrophy of HIV patients on protease inhibitors (Ann. Int. Med. 133: 304, 2000).

Type II diabetes is now rampant in the third world and many of our own First American peoples.

There is probably even more type II diabetes in the poor nations today than in the U.S.

Until recently, the tendency was to blame the western diet ("the poor nations have been coca-colonized": (Nature 357: 362, 1992). I have always taught that the real reason is that the world's poor are much better-fed than in the past, and most no longer lead lives of constant hard physical labor. Stay tuned.

Of course, there has been stronger natural selection against diabetes in countries like the U.S. and Western Europe that have been well-fed for centuries. And in societies with episodes of famine, there is a strong selection bias for type II diabetic body chemistry (i.e., a tendency to hang onto carbohydrate calories), and little chance to express the phenotype.

Whether or not it's related, unborn children exposed to famine have a much stronger tendency to develop type II diabetes when they grow up: Lancet 351: 173, 1998.

* The Pima Indians present a special problem; their rate of diabetes is extremely high with a host of different genetic mutations for insulin resistance (update Diabetes 53: 1181, 2004).

By age 65, the following percentages of U.S. ethnic groups have diabetes:

Hispanics 33% Blacks 25% Whites 17%

The pathophysiology of type II diabetes is fairly well understood.

In type II diabetes, basal insulin secretion is generally normal. In response to glucose administration, insulin secretion may be abnormally low, normal (rare), abnormally high, or delayed ("too much, too late").

Most Type II diabetics have insulin resistance in both liver and skeletal muscle, and this appears to be the key lesion. In addition, however, there is almost always some evidence of beta cell dysfunction.

The liver continues to make and put out glucose (gluconeogenesis) when blood sugar is high, and fails to take up orally-administered glucose. The skeletal muscles fail to take up glucose in response to insulin.

The amount of insulin resistance is modified by obesity and physical conditioning. There's also the baffling combination of gut polypeptides, prostaglandins, beta-endorphins, etc., etc....

You already know "the metabolic syndrome / metabolic syndrome X" (truncal obesity, insulin resistance, dyslipidemia). The cause remains obscure.

The most recent suspect is resistin, produced (at least in mice) by adipocytes, and able to render muscle and liver resistant to the effects of insulin (NEJM 345: 1345, 2001). It's produced especially well by the abdominal and omental adipocytes; this may explain the special risk of "central obesity".

* Liposuction completely fails to alter the metabolic abnormalities caused by obesity (NEJM 350: 2549, 2004).

Two other players in the complex business of insulin resistance is a pair of little-known hormones, amylin ("islet-amyloid polypeptide", "IAPP", pumped out of beta cells along with insulin) and * calcitonin-gene related polypeptide (CGRP, h-CGRP, from nerve and gut), both acting on skeletal muscle to increase its resistance to insulin (PNAS 88: 7713, 1988). * They act on the same receptor, which is not present in fat or parenchymal cells (Diabetes 40: 395, 1991; Diabetes 40(S1): #267, #255, several others, 1991).

Amylin has been reported to be greatly increased in the serum of some type II diabetics. Excreted through the kidneys, it also might account for some of the insulin resistance in renal failure. See Diabetes Care 39(S1): A111-A113, 1990.

More recently, many workers have concluded that neither hormone is present in sufficient quantities to exert an important physiological effect in asymptomatic or diabetic humans (Diabetes 40: 305 & 310, 1991). Nevertheless, the hormones have been conserved over mammalian evolution for some reason, and assays and preparations are poorly-standardized (late 1990). Amylin update Lancet 341: 1249, 1993.

Most recently, genetically scrambled mice who overexpress amylin do get hyperglycemic, with a syndrome much like human type II diabetes (Proc. Nat. Acad. Sci. 93: 3492, 1996). Definitely stay tuned.

I predict that when the underlying cause of type II diabetes (i.e., simultaneous insulin resistance and aberrant insulin production) is worked out, it will prove to be primarily a mitochondriopathy. Stay tuned.

The "Somogyi phenomenon" is a rebound hyperglycemia from all the stress hormones that pour out when the blood glucose drops too low from too much insulin. If a diabetic is hungry, gaining weight, and feeling crummy, consider reducing the insulin levels.

The "dawn phenomenon, i.e., hyperglycemia and insulin resistance in the morning without previous "Somogyi" hypoglycemia, is due to the high output of hGH during while you're finishing up your sleep in the morning.

* WARNING: Many clinicians use the term "insulin resistance" to refer instead to hard-to-manage diabetics of any type who require more than 200 units of insulin daily (a whopping dose). Many of these patients ave antibodies against insulin, while others have severe type II diabetes or any of several other problems. See NEJM 315: 212, 1987.

Hyperosmolar nonketotic diabetic coma (HNKK, HONK) is the usual cause of "diabetic coma" in Type II diabetics (see Arch. Int. Med. 147: 499, 1987), though most of them never get it.

Classically, some acute stress (often the 'flu) increases the demand on the Type II diabetic's struggling beta cells, and the supply of insulin is exhausted. Plasma glucose levels suddenly go extremely high, causing osmotic diuresis, electrolyte disturbances, and death.

Or the illness may simply cause dehydration, producing a vicious cycle with insulin resistance, stress hormones, soaring glucose levels, and ongoing dehydration.

Ketoacidosis is uncommon in type II diabetes, but can occur.

SECONDARY DIABETES has many etiologies

Pancreatic diabetes: destruction of the islets by disease of the exocrine pancreas.

Causes: pancreatitis, carcinoma, hemochromatosis ("bronze diabetes" -- don't overlook this one!), trauma, surgery, etc. etc.

Endocrine diabetes: glucose intolerance due to other endocrine disturbances

Causes: Cushing's syndrome (from any cause), acromegaly, amylin from pancreatic cancer, obesity (??), stress, amylin production by cancer of the pancreas (see above), etc. etc. It would be logical to place pregnancy here too, though it is officially classed elsewhere.

Some people put the one-gene insulin resistance syndromes here.

Rarely, people make autoantibodies that block insulin receptors (South. Med. J. 92: 717, 1999). Update J. Clin. Endo. Metab. 89: 2222, 2004; contrary to popular belief, acanthosis nigricans in a young diabetic (while commonly seen) does not imply antibodies to insulin receptors.

Of course acanthosis nigricans is a darkening and thickening of the epidermis in the armpits and groin. When not part of a paraneoplastic syndrome, it is usually a marker for insulin resistance of some cause; however the underlying basic biology remains elusive.

REMEMBER: Regardless of the cause of the prolonged hyperglycemia, we now know that the complications in remote organs (arteries, eyes, kidneys, nerves) will be the same.

ANATOMIC PATHOLOGY OF DIABETES MELLITUS: These are usually the effects, rather than the causes, of hyperglycemia.

DIABETIC BLOOD VESSEL DISEASE

LARGE VESSEL DISEASE ("macroangiopathy"): accelerated atherosclerosis

Diabetics have a variety of poorly-understood disturbances of lipid metabolism. Nonenzymatic glycosylation of lipoproteins seems to be a problem, LDL's stick best to glycosylated collagen, etc., and glycation products (when they bind to their special receptors in the intima) cause the production of fibrous tissue.

The result is the rapid development of severe atherosclerosis, with strokes, gangrene of the lower extremities, and myocardial infarcts taking their toll, often early in life. Of course, this is all much worse if the diabetic also smokes cigarets.

Good glycemic control does help the accelerated atherosclerosis, confirming the idea that it's due largely to the accumulation of advanced glycation products which cause collagen production.

Big news: Administering the soluble form of the glycation product receptor seems to stop the accelerated atherosclerosis. Definitely stay tuned. Nature 4: 1025, 1998.

{09378} diabetic gangrene {48076} diabetic gangrene {48022} diabetic ulcer {48023} diabetic ulcer {48150} diabetic ulcer

Diabetic gangreneCornell

SMALL VESSEL DISEASE ("microangiopathy"): hyaline arteriolar sclerosis

This is a complex problem.

The basement membrane of the capillaries and the arterioles becomes much thicker ("hyaline arteriolar sclerosis"). Its expansion eventually compromises the lumen of the vessels.

Not surprisingly, these vessels are relatively inelastic, and this is an early, important problem: Br. Med. J. 312: 744, 1996.

Even if the lumen is not badly compromised and the wall isn't excessively stiff, the small vessels of diabetics open and close chaotically, and proper tissue perfusion cannot be assured.

Additionally, the pericytes can proliferate (especially in the glomeruli, where pericytes are called "mesangial cells") or die off (especially in the retina, where pericytes are called "mural cells"). This causes trouble at both sites.

* Endothelial cells can also proliferate, narrowing the lumen further.

* Other factors that are cited are the over-sticky platelets of diabetics, increased blood viscosity, increased RBC rigidity, and increased numbers of free radicals.

Microangiopathy augments the ischemia caused by atherosclerosis, which is why so many diabetics lose legs. It may account for other problems also.

Yes! Tight diabetic control reduces and even reverses microangiopathy. See NEJM 309: 1546 & 1551, 1983, and many others since.

Most diabetics eventually become hypertensive. Nobody knows why, but inability to handle sodium seems essential: Am. J. Med. Sci. 307(S1): S-53, 1994.

Many diabetics are greatly troubled by congestive heart failure as the disease progresses, and perhaps nonenzymatic glycosylation of the heart muscle proteins itself is part of the problem, since even if you control for other factors, poor glycemic control correlates strongly with the development of CHF (Circulation 103 2668, 2001).

DIABETIC KIDNEY DISEASE ("diabetic nephropathy"; Disease-A-Month 44: 214, 1998; NEJM 341: 1127, 1999):

Renal failure causes much disability and death among type I diabetics; this is now the #1 single cause of end-stage renal disease in the U.S. Type II diabetics generally die of something else before their kidneys fail.

Renal vascular lesions

Arteriolar sclerosis of both afferent and efferent arterioles at the glomerular pole is highly characteristic of diabetes. (The other diseases of renal arterioles, notably common-type high blood pressure, only cause sclerosis of the afferent arteriole.)

* Atherosclerosis of intrarenal arteries is common in diabetics and rare in non-diabetics; it is not the major problem.

Glomerular lesions

Always present:

1. Thickening of the glomerular basement membrane because of increased production of GBM (sometimes called "diffuse glomerulosclerosis").

2. Increased amounts of mesangial matrix (also sometimes called "diffuse glomerulosclerosis"). Increased number of mesangial cells in the early lesion, later decreased as the entire glomerulus is replaced by matrix ("hyalinization" of the glomerulus.)

* 3. The GBM, mesangial matrix, and tubular basement membranes (also thick) are bind albumin and other proteins non-specifically ("all that sticky sugar....")

* These three features, together, are pathognomonic of diabetes mellitus (but you probably knew already....) They occur separately in other diseases.

Often present:

Nodular glomerulosclerosis or (nodular) Kimmelstiel-Wilson disease. Big balls of GBM-mesangial matrix material in the glomerular tufts. Highly characteristic of diabetes.

{08892} KW disease; note balls of hyaline, and thick GBM (i.e., you can actually tell where it is) {17159} diabetes with hyalinized arteriole {16789} diabetic glomerulosclerosis, electron micrograph (thick GBM) {16790} diabetic glomerulosclerosis, electron micrograph (thick GBM) {16791} diabetic glomerulosclerosis, H&E {16792} diabetic glomerulosclerosis, PAS; nice capsular drop too {16793} diabetic glomerulosclerosis, H&E {08893} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis; H&E {08895} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis, PAS {09877} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis {17158} Kimmelstiel-Wilson diabetic nodular glomerulosclerosis {17171} end-stage diabetic glomerulosclerosis

Nodular glomerulosclerosisPAS stain

KU Collection

Nodular glomerulosclerosis

KU Collection

Sometimes present:

* "Fibrin caps" ("exudative lesion", "hyperfiltration lesion") -- hyaline crescents on a glomerular tuft

* "Capsular drops" -- hyaline material on the inside surface of Bowman's capsule (highly characteristic of diabetes.)

Clinically, patients have albuminuria (rarely heavy proteinuria), then renal failure (probably due to the mesangium crunching the glomerular capillaries).

The etiology of diabetic glomerulopathy is complex and poorly-understood. Intrarenal fluid dynamics are involved. We don't even know why the kidneys enlarge in diabetics (NEJM 324: 1662, 1991, still good).

Tight control of blood glucose does seem to benefit these patients, and reduces the hyperfiltration response to amino acids (NEJM 324: 1629, 1991). Patients are now put on ACE-inhibitors and protein-restricted to prevent progression of the renal disease. (Yes, it can regress de to therapy: NEJM 348: 2285, 2003).

* Ace-inhibitor plus a calcium channel blocker works marvellously to prevent diabetic kidney disease: NEJM 351: 1941, 2004.

Other renal lesions in diabetes:

* Thick tubular basement membranes (not a health problem).

* Fatty change of tubular cells (systemic lipid disturbance, not a health problem).

* Glycogen in proximal tubular cells (Armanni-Ebstein lesion, a sign of heavy glycosuria, not itself a health problem).

{46306} Armanni-Ebstein; lots of glycogen in the tubular cells

Kidney infections (gram-negative bacilli causing infection of renal pelvis in pyelonephritis, staphylococci causing cortical infections, candida infections, etc.)

Renal papillary necrosis -- just like it sounds. (* "Baby Robbins" misnames it "necrotizing papillitis". The lesion is seen in diabetes, obstruction, sickle cell disease, Wegener's, or abuse of the analgesic phenacetin.)

{49306} pyelonephritis and papillary necrosis in a diabetic

EYES: Diabetes is the commonest cause of blindness before old age in the US. Review: Lancet 350: 197, 1998.

Cataracts: a variety of types, including some clearly caused by sorbitol deposition (proof Proc. Nat. Acad. Sci. 9: 2780, 1995).

Glaucoma: reason for its being more common with diabetes is uncertain.

Diabetic retinopathy: the most serious diabetic eye problem

Nonproliferative phase (NEJM 322: 978, 1990)

Edema, protein exudates, hemorrhages, microinfarcts ("cotton-wool patches") all indicate vascular problems

Microaneurysms (the first change, and highly characteristic of diabetes): ballooning of capillaries where perhaps a pericyte has come off.

{09365} diabetic retinopathy; hemorrhages and exudates {22036} diabetic retinopathy; microaneurysms {22039} diabetic retinopathy {22042} diabetic retinopathy, notice the hemorrhages {22045} diabetic retinopathy -- bleed {22904} microaneurysm {23156} cotton wool patches {23180} diabetic retinopathy {23183} diabetic retinopathy

Proliferative phase: new vessels grow, eventually invading vitreous humor, with hemorrhage, granulation tissue, fibrosis, retinal detachment. These patients get photocoagulation.

{09366} proliferative retinopathy {22895} proliferative retinopathy {22901} proliferative retinopathy -- "scar contracts" and tears off the retina

The molecular biology remains puzzling. Sudden normalization of a poorly-controlled diabetic's glucose can accelerate proliferative retinopathy (Arch. Ophth. 116: 874, 1998).

OTHER PROBLEMS FOR DIABETICS

Infections (bacterial and fungal)

Why diabetics get more infections is still poorly-understood. Candida may thrive on the glucose, hyperglycemia slows down polys, poor circulation keeps the body from fighting infection, etc., etc.).

{48090} diabetic abscess {48091} diabetic abscess

Gallstones (made of cholesterol; nobody knows why these are more common in diabetics, but the average gallbladder volume is much higher in non-insulin-dependent diabetics, perhaps promoting stasis and nidation: Dig. Dis. Sci. 43: 344, 1998.)

Altered platelet function (significance?)

Complications of pregnancy -- all the common problems are commoner in diabetic mothers, and babies are bigger (partly the hyperglycemia, probably partly some growth factor or other: Br. J. Ob. Gyn. 103: 427, 1996) and at extra risk for a variety of birth defects (all of which seem to be preventable by euglycemia through pregnancy).

Diabetic xanthomas (yellow skin bumps -- pseudotumors made of lipid-laden macrophages), necrobiosis (focal necrosis of the dermis), and many other skin abnormalities

Diabetic skinLecture notes and

some great photos

* One team found that nonenzymatic glycosylation actually altered keratinocyte surface receptors so they could not take up glucose. This may have something to do with the poor epidermal healing and some of the other changes (Diabetes 50: 1627, 2001).

{12214} necrobiosis lipoidica diabeticorum

* Hepatic fatty change, even in sober diabetics. Probably this has to do with Syndrome X. Stay tuned.

* Scleredema -- pseudosclerodermatous changes over the back and shoulders caused by accumulation of glycosaminoglycans. This may be a marker for longstanding poor control.

* "Diabetic dermopathy" is purple-brown patches on the shins (less often, the upper legs and/or forearms) which may grow to coalesce. This supposedly has something to do with the microangiopathy and may be seen in other situations with vascular insufficiency.

Chronic hyperglycemia results in non-enzymatic glycosylation of many body proteins.

Hemoglobin A1c is glycosylated hemoglobin which can be measured in the blood to assess the quality of diabetic control (though, of course, home blood glucose testing several times a day by a highly motivated patient is even better....)

We pathologists like to see you order a hemoglobin A1c on stable patients twice a year, with the target of a final HgbA1c value <7%. Arch. Path. Lab. Med. 215: 191, 2001.

The literature is suddenly exploding with talk about "advanced glycosylation (glycation) products", i.e., proteins which have undergone a series of reactions with glucose. For one thing, at least some human cells have a surface receptor for these products, which then activate genes in blood vessels (Proc. Nat. Acad. Sci. 91: 8807, 1994) and glomeruli (Proc. Nat. Acad. Sci. 91: 9519, 1994; Diabetes 44: 824, 1995).

Hemoglobin A1c is an obvious choice for a diabetes screening device, and has been studied as such (JAMA 276: 1264, 1996); it's still not in common use.

* ADDITIONAL INFORMATION ABOUT DIABETES

Much more about the laboratory diagnosis of diabetes and hypoglycemia is available from your lecturer. Phone me when you're on rotations if I can help you with a diabetes-related problem. Some current articles:

J. Clin. Endo. Metab. 85: 1584, 2000. Glycogen synthetase is deficient in diabetic muscle, but contrary to older reports, this is probably the result rather than the cause of type II diabetes.

NEJM 346: 393, 2002. Exercise can actually forestall the development of type II diabetes; apparently, the more, the better; supports many other studies, and better than metformin.

Br. Med. J. 318: 1169, 1999. the current pop claim that hemophilus influenzae B vaccine causes diabetes in children doesn't hold up.

NEJM 350: 1398, 2004. The current claims that immunization causes diabetes are examined in a massive Danish study. Intense scrutiny of kids who did and did not get each of the common vaccines shows no apparently difference in the risk for diabetes.

It takes only a few seconds to make up a lie. It takes years [and in this case, millions of dollars] to refute it. And even then, people still adopt their "most cherished beliefs" on emotion. -- Ed.