Diabetes mellitus

Diabetes mellitus

(Parte 1 de 8)

Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, p 1–2

Introduction

Diabetes mellitus and its complications are clinical conditions of growing importance both from the clinical as well as epidemiological standpoint. The relevance of diabetes at clinical and individual level is given by its lifethreatening acute complications and, especially, by its chronic complications affecting several organs and systems, with increased risk for ocular, renal, cardiac, cerebral, nervous and peripheral vascular diseases. The high prevalence of diabetes in many developed countries or in special ethnic groups, entailing premature disability and mortality, points to its relevance at population level. It is, therefore, mandatory for both the specialist and the practitioner to be acquainted with the pathophysiological mechanisms, clinical manifestations and, above all, therapy of diabetes mellitus.

Recent data showing that control of hyperglycemia may prevent the onset or slow down the progression of complications point to the importance of an appropriate and efficacious treatment. Indeed, the aim of this book is to serve as a tool to provide physicians with the latest views on diagnostic aspects and pathophysiological mechanisms as a premise to go deep into the various facets of the modern management of diabetes.

This book begins with introductory chapters on classification and clinical aspects, after which an account is given of insulin secretion as modulated by sulfonylureas and of insulin resistance (in its genetic and acquired components) as modified by diet and the new lipase-inhibitory drug or by metformin (and perhaps troglitazone agents). Insulin therapy of both type 1 and, when required, type 2 diabetes is adequately covered. This is followed by an integrated view of metabolic control, including combined therapy and self-monitoring, in the light of the lesson from DCCT (Diabetes Control and Complications Trial) and UK-PDS (United Kingdom Prospective Diabetes Study).

The mechanisms of complications are treated as an introduction to the understanding of possible therapeutic strategies. Then retinopathy, nephropathy, hypertension and cardiovascular disease are considered in their clinical aspects and therapeutic interventions. Extensive space is devoted to the various neuropathic manifestations, including erectile dysfunction, as well as to the foot problems. Final chapters highlight the need for multifactorial treatment and the clinical and therapeutic problems of diabetic pregnancy.

The international panel of authors has made any effort to condense this rich content into a relatively short text and to present it in a clear and smoothto-readform.Whilemoreextensiveinformationmaybefoundinlargertreatises (see Suggested Reading, below), we hope that this medium-size book will be useful to all physicians interested in the management of diabetic patients by providing them with a simple yet updated source of information concerning the New Concepts in Diabetes and Its Treatment.

Francesco Belfiore Carl Erik Mogensen

SuggestedReading

Alberti KGMM, Zimmet P, DeFronzo RA: International Textbook of Diabetes mellitus, ed 2. Chichester,

Belfiore F (ed): Frontiers in Diabetes. Basel, Karger, vol 8/1987, vol 9/1990, vol 10/1990, vol 1/1992, vol 12/1993, vol 14/1998.

Bray G, Bouchard C, James WPT (eds): Handbook of Obesity. New York, Dekker, 1997. Kakn CR, Weir GC (eds): Joslin’s Diabetes mellitus, ed 13. Malvern, Lea & Febiger, 1994. Mogensen CE (ed): The Kidney and Hypertension in Diabetes mellitus, ed 5. Boston, Kluwer Academic, 2000.

Pickup JC, Williams G (eds): Textbook of Diabetes, ed 2. Oxford, Blackwell, 1997. Porte D Jr, Sherwin RS (eds): Ellenberg and Rifkin’s Diabetes mellitus, ed 4, Amsterdam, Elsevier, 1990, and ed 5, Old Tappan/NJ, Appleton & Lange, 1996.

2Introduction

ChapterI

Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, p 3–19

EtiologicalClassification, Pathophysiology andDiagnosis

Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Introduction

According to the classical definition, diabetes mellitus is a disorder resulting from both genetic predisposition and favoring environmental factors, and is characterized by alterations in the metabolism of carbohydrate, fat and protein,whicharecausedbyarelativeorabsolutedeficiencyofinsulinsecretion and different levels of insulin resistance. In the patients with long-standing diabetes, late complications develop consisting of alterations and failure of various organs (especially the noninsulin-sensitive ones) including the eyes (retinopathy with vision loss), kidneys (nephropathy leading to renal failure), nerves (peripheral and autonomic neuropathy), heart and blood vessels (precocious and severe cardiovascular, cerebrovascular and peripheral vascular atherosclerosis). Diabetes mellitus includes etiologically and clinically different diseases that have hyperglycemia in common, representing a syndrome rather than a single disease.

Until 1997, the classification and diagnosis of diabetes were based on the criteria developed by an international work group, sponsored by the National Diabetes Data Group (NDDG) of the American National Institute of Health, and published in 1979. The World Health Organization (WHO) Expert Committee on Diabetes in 1980 and the WHO Study Group on Diabetes mellitus in 1985 adopted the recommendations of the NDDG with slight alterations. In 1995, an International Expert Committee was established (sponsored by the American Diabetes Association) with the aim to review the scientific literaturesince1979andtodecidetheadequatechangesintheclassificationand diagnostic criteria of diabetes. The committee work culminated in a document published in 1997, divided into four sections (definition and description of diabetes, classification of diabetes, diagnostic criteria and testing for diabetes), which we summarize in this chapter.

DefinitionandDescriptionofDiabetesmellitus

The basis of the metabolic alterations in diabetes is the reduction (to a various degree) of insulin action on insulin-sensitive tissues, due to deficiency of insulin secretion or to insulin resistance or both. The majority of cases of diabetes mellitus falls into two major forms: type 1 and type 2 diabetes.

Type 1 Diabetes

Immune-Mediated Type 1 Diabetes Type 1 diabetes (previously also named insulin-dependent diabetes mellitus – IDDM – or juvenile-onset diabetes) is an immune-mediated form of diabetes, which accounts for approximately 5–10% of all diabetics in the Western world. It occurs mainly in healthy nonobese children or young adults but may also affect subjects at any age, and results from an absolute deficiency of insulin secretion (evidenced by low or undetectable levels of plasma C- peptide), caused by a cellular-mediated autoimmune destruction of pancreatic b-cells. Although the affected subjects are usually nonobese, the presence of obesity is not incompatible with the diagnosis of type 1 diabetes. The course may be rapid in children and young adults, slower in older patients. Adult patients can retain for some time a residual b-cell function while children and adolescents often show early the effects of severe insulin lack, with a diabetes appearing abruptly over days or weeks and rapidly progressing to acute lifethreatening complication (ketoacidotic coma), which may be the first manifestation of the disease, particularly in presence of precipitating factors such as infections or other stress.

Genetic Predisposition. Type 1 diabetes is favored by a not yet fully understood genetic predisposition, linked to the HLA system. Pedigree studies of type 1 diabetes families have shown a low prevalence of direct vertical transmission. However, the risk to develop the disease for children who are first-degree relatives of type 1 diabetic patients is between 5 and 10%, the risk being increased when there is haploidentity with the affected sibling and even more when there is HLA identity. It has also been observed that the risk is 5-fold higher for children of a diabetic father compared to children of a diabetic mother (sexual imprinting). Candidate genes for type 1 diabetes have been

4Belfiore/Iannello suggested to occur in chromosomes 2, 6, 1 and 15. However, the major gene seems to be located at the HLA locus in the chromosome 6. Indeed, it is now largely accepted that type 1 diabetes is strongly associated to HLA system, especially with the class I molecules which encode for the D allele. Patients who express the DR3 or DR4 alleles or those who are heterozygous (DR3/ DR4) are especially susceptible to type 1 diabetes. Class I alleles (B8, B15) also seem to be associated to type 1 diabetes as they show linkage disequilibrium, i.e. show nonrandom association with the D alleles. Recently, great importance has been attributed to the DQ locus. It has been shown that DQb1*0301 and DQb1*0302 segregate with DR4 and that DQb1*0201 segregates with DR3. Presence of DQb1*0201 and DQb1*0302 or, especially, the heterozygous state DQb1*0201/0302 entails high risk. On the other hand, DQb1*0502 and DQb1*0602 are associated with the DR2 haplotypes and would be protective.

Immunologic Mechanisms. Class I molecules are expressed by macrophages,endothelialcellsandlymphocytes,andarerequiredforthepresentation of an antigen to the regulatory T cells, which become activated, thus triggering the immune response. In other words, the favoring HLA haplotypes indicated above permit the interaction of environmental factors (such as certain viral infections or chemical agents) with specific cell membrane components (the HLA molecules), which results in the presentation of the antigen to the regulatory T lymphocytes, thus triggering an autoimmune mechanism. Several viral infections have been suggested as favoring type 1 diabetes, including Coxsackievirus infections, infectious mononucleosis, mumps, congenital rubella, hepatitis and encephalomyocarditis. Some toxins have also been implicated. Consumption of cow’s milk during the early life may be an important environmentalfactorassociatedwith type1diabetesdevelopmentand,because the role of bovine albumin in the induction of b-cell autoimmunity have not been confirmed, b-casein has been suggested as the responsible protein. Virus, toxins, or other factors may directly damage b-cells or favor apoptosis (programmed cell death), or may expose cryptic antigen to the immune system, or may act through molecular mimicry (exogenous molecules similar in amino acid sequence to some endogenous molecules), or they may induce expression of class I molecules in the b-cells (which therefore would become antigenpresenting cells, able to trigger the autoimmune response). An alternative hypothesis which does not rely on exogenous antigen postulates a defective removal of autoreactive T cells, which normally are destroyed in the thymus in the early life. In contrast to the most common form of type 1 diabetes, linked to environmental factors (formerly called type IA), in approximately 10% of all cases of type 1 diabetes (more frequently in females, with HLADR3, from 30 to50 years of age), the disease is a primary autoimmune disorder (previously called type IB) and is associated to other endocrine and nonendo-

5Etiological Classification, Pathophysiology and Diagnosis crine autoimmune diseases (Grave’s disease, Hashimoto’s thyroiditis, Addison’s disease, primary gonadal failure, vitiligo, pernicious anemia, connective tissue disease, celiac disease, myasthenia gravis, etc.). This primary autoimmune pathogenesis seems to be confirmed by a persistence of islet cell autoantibodies (ICAs) forever. In 85–90% of patients, diabetes is early associated with one or more serological genetic markers such as ICAs, IAAs (insulin autoantibodies),

GAD65 (autoantibodies to glutamic acid decarboxylase) and IA-2 or IA-2b (autoantibodiestotyrosinephosphatase). Theseautoantibodiesdisappearover the course of a few years in the majority of patients, and may be the result rather than the cause of the autoimmune process.

Clinical Picture. Manifest type 1 diabetes is characterized by symptoms linked to the marked hyperglycemia, such as polyuria (due to the osmotic effect of glucose), polydipsia (to compensate for the water lost with polyuria), polyphagia (to compensate for the energetic substrate glucose lost in the urine), weight loss and fatigue (due to loss of glucose in urine and to dehydration), andblurredvision(duetolensosmoticdisturbances).Thesepatientsareinsulindependent for their survival and prone to ketosis; impairment of growth, susceptibility to certain infections, hypertension, lipoprotein metabolism alterations, periodontal disease and psychosocial dysfunctions are frequent.

Idiopathic Type 1 Diabetes The idiopathic diabetes includes some forms of type 1 diabetes (common in individuals of African and Asian origin) due to unknown etiology, with strong genetic inheritance (not HLA-associated), without markers of autoimmunity. There is severe deficit of insulin secretion and tendency to ketoacidosis, with absolute requirement of insulin therapy.

Pathophysiology of Type 1 Diabetes The pathophysiological changes occurring in type 1 diabetes as a consequenceofthesevereinsulindeficiencymaybebetterunderstoodbycomparing the normal picture of the main metabolic pathways, as summarized in figure 1, with the abnormal situation present in type 1 diabetes, outlined in figure 2 (see also chapter I on Insulin Resistance). In type 1 diabetes, the deficit of insulin and the prevalence of counterregulatory hormones, primarily glucagon, leads to the activation of glycogenolysis and gluconeogenesis in liver, with ensuing enhanced hepatic glucose output (HGO). In addition, the deficiency in insulin actionresultsinreducedglucoseutilizationinperipheralinsulinsensitivetissues (primarilymuscle)aswellasinactivationoflipolysisintheadiposetissue(insulin normallyexertsanantilipolyticeffect),withenhancedreleaseofFFA.Thelatter, althoughtheycannotbedirectlyconvertedintoglucoseinman,favorgluconeogenesisintheliver.CombinationofenhancedHGOandreducedglucoseutiliza-

6Belfiore/Iannello

Fig. 1. Scheme showing the main metabolic pathways of intermediate metabolism in the three insulin-sensitive tissues (liver, muscle and adipose tissue) participating in the metabolic homeostasis. Note that most metabolic pathways are opposed to each other to form couples composed of a ‘forward pathway’ and a ‘backward pathway’, thus allowing substrate cycling. Examples are: glycogen synthesis and glycogenolysis (steps 1 and 2 in liver, 1 and 12 in muscle), glycolysis and gluconeogenesis (steps 5 and 6), triglyceride synthesis and hydrolysis (lipolysis) (steps 17 and 18 in adipose tissue; 26 and 27 in liver), protein synthesis and proteolysis (steps 13 and 14), etc. Some cycles are ‘inter-tissular’, linking liver and muscle, such as the Cori cycle (expanded to include alanine in addition to lactate and pyruvate), composed of steps 10, 6, 3, 8 and 9, pertaining to carbohydrate metabolism, as well as the cycle linking liver and adipose tissue (steps 19, 2, 26, 28 and 29), pertaining to lipid metabolism. In the normal state, blood glucose is kept at the normal level through a balance between hepatic glucose production (step 3) and glucose utilization by peripheral tissues, mainly the muscle (step 8). VLDL and triglycerides are kept normal through a balance between hepatic production (step 28) and peripheral degradation by LPL, primarily at adipose tissue level (step 29). Ketones are not present because Ac-CoA is entirely oxidized to CO2 (or utilized for the synthesis of FFA – step 24).

tion results in hyperglycemia. In addition, FFA exert anti-insulin effects at the muscle level, through the mechanism of the glucose-FFA cycle (Randle’s cycle), which may cause resistance to the therapeutically administered insulin (see the chapter on Insulin Resistance). It should also be considered that hyperglycemia itselffavorsglucoseutilization(glucoseeffectiveness),perhapsbyactingonnoninsulin-dependent glucose transporters (GLUT1 in gut, GLUT2 in liver and GLUT3inbrain),andthatintype1diabetesthisglucoseeffectmaybereduced, i.e. there may be ‘glucose resistance’.

7Etiological Classification, Pathophysiology and Diagnosis

Fig. 2. Scheme of the main metabolic pathways (similar to that outlined in figure 1) and of their changes in activity rate occurring in states of severe insulin deficiency, such as decompensated type 1 diabetes (thick or thin arrows indicate increased or decreased activity, respectively). Note the prevalence of the catabolic pathways over the anabolic ones: glycogenolysis over glycogen synthesis (steps 2 and 1 in liver, steps 12 and 1 in muscle), gluconeogenesis over glycolysis (steps 6 and 5), triglyceride hydrolysis or lipolysis over triglyceride synthesis (steps 17 and 18), proteolysis over proteosynthesis (steps 14 and 13), etc. Concerning the ‘inter-tissural’ cycles, note the prevalence of hepatic glucose production (step 3) over glucose utilization (step 8), leading to glucose accumulation in blood (unnumbered arrow starting from glucose). The enhanced hepatic glucose production (step 3), effected by the enzyme glucose-6-Pase, utilizes glucose-6-P in part derived from glycogen (step 2) but mainly formed through the gluconeogenic process (step 6) which in turn utilizes the gluconeogenic precursors (pyruvate, lactate and alanine) coming from the muscle (step 10), where they are mainly produced from amino acids (step 15) derived from the enhanced proteolysis (step 14). Note the overall process of conversion of protein to glucose (steps 14, 15, 10, 6 and 3), and consider that some amount of the glucose-6-P formed through the gluconeogenic process may be converted into glycogen (this latter conversion being favored by cortisol). With regard to the FFA-VLDL cycle, linking liver and adipose tissue, note the enhanced FFA release from adipose tissue (step 19), the enhanced afflux of FFA to muscle (step 20), where they are oxidized (step 21) and oppose the oxidation of glucose-derived pyruvate (glucose-FFA cycle, see the text), thus inducing insulin resistance. Note also the hyperafflux of FFA to the liver, where they may be reesterified to triglycerides (step 26) or b-oxidized to Ac-CoA (step 23). The triglycerides so formed may be deposited in the hepatocytes (steatosis) or may be incorporated into VLDL which are secreted into the circulation (step 28), leading to the marked hypertriglyceridemia of the decompensated diabetes. The large amount of Ac-CoA produced by b-oxidation of FFA cannot be entirely oxidized in the Krebs cycle (also for the relative deficiency of oxalacetate, which is diverted towards gluconeogenesis) and is converted into ketone bodies (step 25) leading the ketoacidosis. Thus, in the diabetic state, blood glucose is elevated because hepatic glucose production (step 3) prevails over glucose utilization

8Belfiore/Iannello

Type 2 Diabetes

Type 2 diabetes (previously also named non-insulin-dependent diabetes mellitus – NIDDM – or adult-onset diabetes) occurs in approximately 90–95% of diabetic people in the Western world, resulting from insulin resistance and insufficient compensatory insulin secretion. The disease has an insidious onset and remains asymptomatic and undiagnosed for a long period, even if the moderate hyperglycemia is able to induce severe diabetic late complications.

Type 2 diabetes is strongly favored by genetic predisposition. However, although it shows familial aggregation as well as a high concordance (80%) in monozygotic twins, its mode of inheritance is not fully understood. It may well be a polygenic disease. In any case, the risk of offspring and siblings of type 2 diabetic patients to develop the disease is relatively elevated.

In addition to the genetic predisposition, favoring environmental factors are involved, such as excessive caloric intake, obesity with increased body fat in the abdominal (visceral) site, sedentary habit, etc. The insulin levels may be normal or even increased (especially in presence of obesity) for a long time, but may decrease in the late stage of the disease. The abnormal carbohydrate metabolism can be early identified measuring fasting glycemia (FPG) or performing an oral glucose tolerance test (OGTT). This type of diabetes is noninsulin-dependent for survival and is nonketosis prone. Hyperglycemia is usually improved or corrected by diet, weight loss and oral hypoglycemic drugs. In type 2 diabetics an acute life-threatening complication, the nonketotic hyperosmolar coma, can develop whereas ketoacidosis seldom occurs spontaneously, although it may arise during stress, infections or other illnesses.

Pathophysiology of Type 2 Diabetes This disease is due to a varying combination of insulin resistance and reduction (especially in the late stage of the disease) in insulin secretion (see chapter I on Insulin Secretion and chapter II on Insulin Resistance). The metabolic alterations are less pronounced than those in type 1 diabetes, outlined in figure 2 (see also chapter I on Insulin Resistance). Due to insulin resistance (and to enhanced counterregulatory hormones), there is increased HGO (which contributes primarily to fasting hyperglycemia) and reduced peripheral glucose utilization. There is also elevation of plasma FFA (resulting fromactivationoflipolysisand/ortheoftenenhancedfatmassduetocoexisting by peripheral tissues, mainly the muscle (step 8). VLDL and triglycerides are increased because hepatic production (step 28) prevails over peripheral degradation by LPL, primarily at the adipose tissue level (step 29). Ketones are formed at high rate (step 25) because the large amount of Ac-CoA cannot be entirely oxidized to CO2.

9Etiological Classification, Pathophysiology and Diagnosis obesity), which in turn contributes to insulin resistance through the mechanism of the glucose-FFA cycle. As mentioned above (under Type 1 Diabetes), hyperglycemia itself favors glucose utilization (glucose effectiveness). This mechanism may be impaired in type 2 diabetes, i.e. ‘glucose resistance’ may be present. It has been observed that in obesity and type 2 diabetes (as well as in acromegaly and Cushing’s disease),in the postabsorptive period, noninsulinmediated glucose uptake is a major determinant of glucose disposal and is similar in the different pathologies studied. On the other hand, although absolute rates of basal insulin-mediated glucose uptake are reduced in insulinresistant states, they do not achieve statistical value compared with control subjects because of compensatory hyperinsulinemia.

Other Specific Types of Diabetes

Various, less common, types of diabetes are known to occur, in which the secretory defect is based upon different mechanisms.

Genetic Defects of b-Cell Function The maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of noninsulin-dependent diabetes, characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. There is no HLA association nor evidence of cell-mediated autoimmunity. It has been estimated that 2–5% of patients with type 2 diabetes may have this form of diabetes mellitus. However, the frequency of MODY is probably underestimated. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic b-cell dysfunction, rather than insulin resistance, is the primary defect in this disorder. To date, three MODY genes have been identified.

MODY-1. Studies in an affected family showed that the gene responsible for MODY-1 is tightlylinked to the adenosine deaminase geneon chromosome 20q. Further research has shown that responsible for MODY-1 is a mutation in the gene-encoding hepatocyte nuclear factor (HNF)-4a, a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1a expression.

MODY-2. This form is due to mutations in glucokinase (GK – see chapter

(Parte 1 de 8)

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