New Concepts in Diabetes and Its Treatment - part 1 ppt

published in 1997, divided into four sections definition and description ofdiabetes, classification of diabetes, diagnostic criteria and testing for diabetes,which we summarize in this c

affecting several organs and systems, with increased risk for ocular, renal,cardiac, cerebral, nervous and peripheral vascular diseases The high preva-lence of diabetes in many developed countries or in special ethnic groups,entailing premature disability and mortality, points to its relevance at popula-tion level It is, therefore, mandatory for both the specialist and the practitioner

to be acquainted with the pathophysiological mechanisms, clinical tions and, above all, therapy of diabetes mellitus

manifesta-Recent data showing that control of hyperglycemia may prevent the onset

or slow down the progression of complications point to the importance of anappropriate 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 andpathophysiological 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 clinicalaspects, after which an account is given of insulin secretion as modulated bysulfonylureas and of insulin resistance (in its genetic and acquired components)

as modified by diet and the new lipase-inhibitory drug or by metformin (andperhaps troglitazone agents) Insulin therapy of both type 1 and, when re-quired, type 2 diabetes is adequately covered This is followed by an integratedview of metabolic control, including combined therapy and self-monitoring,

in the light of the lesson from DCCT (Diabetes Control and ComplicationsTrial) and UK-PDS (United Kingdom Prospective Diabetes Study)

The mechanisms of complications are treated as an introduction to theunderstanding of possible therapeutic strategies Then retinopathy, nephrop-athy, hypertension and cardiovascular disease are considered in their clinicalaspects and therapeutic interventions Extensive space is devoted to the variousneuropathic manifestations, including erectile dysfunction, as well as to thefoot problems Final chapters highlight the need for multifactorial treatmentand the clinical and therapeutic problems of diabetic pregnancy.

The international panel of authors has made any effort to condense thisrich content into a relatively short text and to present it in a clear and smooth-to-read form While more extensive information may be found in larger treatises(see Suggested Reading, below), we hope that this medium-size book will beuseful to all physicians interested in the management of diabetic patients byproviding them with a simple yet updated source of information concerning

the New Concepts in Diabetes and Its Treatment.

Francesco Belfiore Carl Erik Mogensen

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.

re-Until 1997, the classification and diagnosis of diabetes were based on thecriteria developed by an international work group, sponsored by the NationalDiabetes Data Group (NDDG) of the American National Institute of Health,and published in 1979 The World Health Organization (WHO) Expert Com-mittee 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 bythe American Diabetes Association) with the aim to review the scientificliterature since 1979 and to decide the adequate changes in the classification anddiagnostic criteria of diabetes The committee work culminated in a document

published in 1997, divided into four sections (definition and description ofdiabetes, classification of diabetes, diagnostic criteria and testing for diabetes),which we summarize in this chapter.

Definition and Description of Diabetes mellitus

The basis of the metabolic alterations in diabetes is the reduction (to avarious degree) of insulin action on insulin-sensitive tissues, due to deficiency

of insulin secretion or to insulin resistance or both The majority of cases ofdiabetes 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 litus – IDDM – or juvenile-onset diabetes) is an immune-mediated form ofdiabetes, which accounts for approximately 5–10% of all diabetics in the West-ern world It occurs mainly in healthy nonobese children or young adults butmay also affect subjects at any age, and results from an absolute deficiency

mel-of insulin secretion (evidenced by low or undetectable levels mel-of plasma peptide), caused by a cellular-mediated autoimmune destruction of pancreaticb-cells Although the affected subjects are usually nonobese, the presence ofobesity is not incompatible with the diagnosis of type 1 diabetes The coursemay be rapid in children and young adults, slower in older patients Adultpatients can retain for some time a residualb-cell function while children andadolescents often show early the effects of severe insulin lack, with a diabetesappearing abruptly over days or weeks and rapidly progressing to acute life-threatening complication (ketoacidotic coma), which may be the first mani-festation of the disease, particularly in presence of precipitating factors such

C-as infections or other stress

Genetic Predisposition Type 1 diabetes is favored by a not yet fully

under-stood genetic predisposition, linked to the HLA system Pedigree studies

of type 1 diabetes families have shown a low prevalence of direct verticaltransmission However, the risk to develop the disease for children who arefirst-degree relatives of type 1 diabetic patients is between 5 and 10%, the riskbeing increased when there is haploidentity with the affected sibling and evenmore when there is HLA identity It has also been observed that the risk is5-fold higher for children of a diabetic father compared to children of a diabeticmother (sexual imprinting) Candidate genes for type 1 diabetes have been

suggested to occur in chromosomes 2, 6, 11 and 15 However, the major geneseems to be located at the HLA locus in the chromosome 6 Indeed, it is nowlargely accepted that type 1 diabetes is strongly associated to HLA system,especially with the class II molecules which encode for the D allele Patientswho 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) alsoseem to be associated to type 1 diabetes as they show linkage disequilibrium, i.e.show nonrandom association with the D alleles Recently, great importancehas 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 II molecules are expressed by

macro-phages, endothelial cells and lymphocytes, and are required for the presentation

of an antigen to the regulatory T cells, which become activated, thus triggeringthe immune response In other words, the favoring HLA haplotypes indicatedabove permit the interaction of environmental factors (such as certain viralinfections or chemical agents) with specific cell membrane components (theHLA molecules), which results in the presentation of the antigen to the regu-latory T lymphocytes, thus triggering an autoimmune mechanism Severalviral infections have been suggested as favoring type 1 diabetes, includingCoxsackievirus infections, infectious mononucleosis, mumps, congenital ru-bella, hepatitis and encephalomyocarditis Some toxins have also been impli-cated Consumption of cow’s milk during the early life may be an importantenvironmental factor associated with type 1 diabetes development and, becausethe role of bovine albumin in the induction ofb-cell autoimmunity have notbeen confirmed,b-casein has been suggested as the responsible protein Virus,toxins, or other factors may directly damageb-cells or favor apoptosis (pro-grammed cell death), or may expose cryptic antigen to the immune system,

or may act through molecular mimicry (exogenous molecules similar in aminoacid sequence to some endogenous molecules), or they may induce expression

of class II molecules in the b-cells (which therefore would become presenting cells, able to trigger the autoimmune response) An alternativehypothesis which does not rely on exogenous antigen postulates a defectiveremoval of autoreactive T cells, which normally are destroyed in the thymus

antigen-in the early life In contrast to the most common form of type 1 diabetes,linked to environmental factors (formerly called type IA), in approximately10% of all cases of type 1 diabetes (more frequently in females, with HLA-DR3, 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-

crine autoimmune diseases (Grave’s disease, Hashimoto’s thyroiditis, Addison’sdisease, primary gonadal failure, vitiligo, pernicious anemia, connective tissuedisease, celiac disease, myasthenia gravis, etc.) This primary autoimmunepathogenesis seems to be confirmed by a persistence of islet cell autoantibodies(ICAs) forever In 85–90% of patients, diabetes is early associated with one ormore serological genetic markers such as ICAs, IAAs (insulin autoantibodies),GAD65(autoantibodies to glutamic acid decarboxylase) and IA-2 or IA-2b(autoantibodies to tyrosine phosphatase) These autoantibodies disappear overthe course of a few years in the majority of patients, and may be the resultrather 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),and blurred vision (due to lens osmotic disturbances) These patients are insulin-dependent for their survival and prone to ketosis; impairment of growth,susceptibility to certain infections, hypertension, lipoprotein metabolism al-terations, 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, withstrong genetic inheritance (not HLA-associated), without markers of autoim-munity 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 sequence of the severe insulin deficiency may be better understood by comparingthe 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 (seealso chapter III on Insulin Resistance) In type 1 diabetes, the deficit of insulinand the prevalence of counterregulatory hormones, primarily glucagon, leads

con-to the activation of glycogenolysis and gluconeogenesis in liver, with ensuingenhanced hepatic glucose output (HGO) In addition, the deficiency in insulinaction results in reduced glucose utilization in peripheral insulin sensitive tissues(primarily muscle) as well as in activation of lipolysis in the adipose tissue (insulinnormally exerts an antilipolytic effect), with enhanced release of FFA The latter,although they cannot be directly converted into glucose in man, favor gluconeo-genesis in the liver Combination of enhanced HGO and reduced glucose utiliza-

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, 11 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, 22, 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 CO 2 (or utilized for the synthesis of FFA – step 24).

tion results in hyperglycemia In addition, FFA exert anti-insulin effects at themuscle level, through the mechanism of the glucose-FFA cycle (Randle’s cycle),which may cause resistance to the therapeutically administered insulin (see thechapter on Insulin Resistance) It should also be considered that hyperglycemiaitself favors glucose utilization (glucose effectiveness), perhaps by acting on non-insulin-dependent glucose transporters (GLUT1 in gut, GLUT2 in liver andGLUT3 in brain), and that in type 1 diabetes this glucose effect may be reduced,i.e there may be ‘glucose resistance’

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:

glyco-genolysis over glycogen synthesis (steps 2 and 1 in liver, steps 12 and 11 in muscle), genesis 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), e ffected 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

gluconeo-to the FFA-VLDL cycle, linking liver and adipose tissue, note the enhanced FFA release from adipose tissue (step 19), the enhanced a fflux 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 hypera fflux 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

in monozygotic twins, its mode of inheritance is not fully understood It maywell be a polygenic disease In any case, the risk of offspring and siblings oftype 2 diabetic patients to develop the disease is relatively elevated.

In addition to the genetic predisposition, favoring environmental factorsare 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 carbohydratemetabolism can be early identified measuring fasting glycemia (FPG) or per-forming an oral glucose tolerance test (OGTT) This type of diabetes is nonin-sulin-dependent for survival and is nonketosis prone Hyperglycemia is usuallyimproved or corrected by diet, weight loss and oral hypoglycemic drugs Intype 2 diabetics an acute life-threatening complication, the nonketotic hyperos-molar 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 andreduction (especially in the late stage of the disease) in insulin secretion (seechapter II on Insulin Secretion and chapter III on Insulin Resistance) Themetabolic alterations are less pronounced than those in type 1 diabetes, out-lined in figure 2 (see also chapter III on Insulin Resistance) Due to insulinresistance (and to enhanced counterregulatory hormones), there is increasedHGO (which contributes primarily to fasting hyperglycemia) and reducedperipheral glucose utilization There is also elevation of plasma FFA (resultingfrom activation of lipolysis and/or the often enhanced fat mass due to coexisting

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 CO 2

obesity), which in turn contributes to insulin resistance through the mechanism

of the glucose-FFA cycle As mentioned above (under Type 1 Diabetes), glycemia itself favors glucose utilization (glucose effectiveness) This mecha-nism may be impaired in type 2 diabetes, i.e ‘glucose resistance’ may bepresent It has been observed that in obesity and type 2 diabetes (as well as

hyper-in acromegaly and Cushhyper-ing’s disease), hyper-in the postabsorptive period, nonhyper-insulhyper-in-mediated glucose uptake is a major determinant of glucose disposal and issimilar in the different pathologies studied On the other hand, althoughabsolute rates of basal insulin-mediated glucose uptake are reduced in insulin-resistant states, they do not achieve statistical value compared with controlsubjects because of compensatory hyperinsulinemia

noninsulin-Other Specific Types of Diabetes

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

Genetic Defects of b-Cell Function

The maturity-onset diabetes of the young (MODY) is a genetically geneous monogenic form of noninsulin-dependent diabetes, characterized byearly onset, usually before 25 years of age and often in adolescence or child-hood, and by autosomal dominant inheritance There is no HLA associationnor evidence of cell-mediated autoimmunity It has been estimated that 2–5%

hetero-of patients with type 2 diabetes may have this form hetero-of diabetes mellitus.However, the frequency of MODY is probably underestimated Clinical studieshave shown that prediabetic MODY subjects have normal insulin sensitivitybut suffer from a defect in glucose-stimulated insulin secretion, suggestingthat pancreaticb-cell dysfunction, rather than insulin resistance, is the primarydefect in this disorder To date, three MODY genes have been identified

MODY-1 Studies in an affected family showed that the gene responsiblefor MODY-1 is tightly linked to the adenosine deaminase gene on chromosome20q Further research has shown that responsible for MODY-1 is a mutation

in the gene-encoding hepatocyte nuclear factor (HNF)-4a, a member of thesteroid/thyroid hormone receptor superfamily and an upstream regulator ofHNF-1a expression

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

II for the functional meaning of GK inb-cells) and is associated with defects

in insulin secretion, reduction in hepatic glycogen synthesis and in the netaccumulation of hepatic glycogen as well as increased hepatic gluconeogenesisfollowing meals, resulting in impaired glucose tolerance or diabetes mellitus

characterized by mild chronic hyperglycemia The hyperglycemia due to GKdeficiency is often mild (fewer than 50% of subjects have overt diabetes)and is evident during the early years of life Despite the long duration ofhyperglycemia, GK-deficient subjects have a low prevalence of micro- andmacrovascular complications of diabetes Obesity, arterial hypertension anddyslipidemia are also uncommon in this form of diabetes.

MODY-3 In several families, this form of MODY was found to be linked

with microsatellite markers on chromosome 12q The disease was estimated to

be linked to this chromosome region in approximately 50% of families in a ogeneity analysis It is the most common form of MODY Affected patients ex-hibit major hyperglycemia with a severe insulin secretory defect, suggesting thatthe causal gene is implicated in pancreaticb-cell function MODY-3 was furthershown to be due to mutations in the gene-encoding HNF-1a (which is encoded

heter-by the gene TCF1) HNF-1a is a transcription factor that helps in the specific regulation of the expression of several liver genes and also functions as

tissue-a wetissue-ak trtissue-anstissue-activtissue-ator of the rtissue-at insulin-I gene

Familial Hyperinsulinemia The high-affinity sulfonylurea receptor, a novelmember of the ATP-binding cassette superfamily, is one component of theATP-sensitive K+ channel The protein is critical for regulation of insulinsecretion from pancreaticb-cells, and mutations in the receptor (or in the KATP

channels) have been linked to familial hyperinsulinemia, a disorder ized by unregulated insulin release despite severe hypoglycemia Other formsmay be due to mutation in the GK gene, leading to a hyperresponsive enzyme

character-Other In addition, a diabetes type associated with deafness may be linked

to point mutations in mitochondrial DNA, and still other forms with lessclearly defined defects are known to occur In about 50% of cases of MODY,the genetic background is uncertain It should be stressed that the role of theabove genes (responsible for b-cell dysfunction) in the susceptibility to themore common late-onset form of type 2 diabetes remains uncertain Geneticstudies seem to exclude any function as major susceptibility genes, althoughthey might play a minor role in a polygenic context or a major role in particularpopulations

Rare Genetic Defects of Insulin Action

These are a heterogeneous group of rare conditions which includes: (a) dromes associated with acanthosis nigricans, which is a brown to almost blackhyperpigmentation of the skin, most often located in the neck, axilla, groin

syn-or other areas, less rare in Blacks syn-or in subjects of Hispanic syn-origin The affectedpatients show high insulin levels Some cases are due to mutation in the insulinreceptor resulting in diminished tyrosine-kinase activity (type A syndrome).Others are due to antibodies to the insulin receptors which prevent insulin

binding (type B syndrome) Interestingly, some cases have been reported inwhich antibodies to the receptor exert an agonistic effect, producing hypoglyce-mia (b) Generalized or partial (face and trunk) lipodystrophies, which may

be congenital or acquired, are characterized by fat depletion, and result fromdecrease in the number or affinity of the receptor for insulin or from postrecep-tor defects Patients show high insulin levels, hyperglycemia (without ketoac-idosis for the scarcity of fat), hypertriglyceridemia (with eruptive xanthomas),enlargement of liver, spleen, heart, and hypertrophy of external genitalia.Lymphadenopathy and hirsutism may also occur as well as varicose veins,mental retardation and kidney involvement In the congenital form, there isalso muscle hypertrophy (c) Leprechaunism syndrome, due to mutation ininsulin receptors (which may be altered in both the a and b subunits andwhose expression in the cell membrane is markedly reduced), and consisting

of insulin resistance associated with severe growth retardation, elfin appearance

of the face, hirsutism, absence of subcutaneous fat and thickened skin.(d) Other rare conditions such as the Werner’s syndrome, the Alstro¨m syn-drome, the Rabson-Mendenhall syndrome (which may be associated withacanthosis nigricans), the pineal hypertrophy syndrome, and the ataxia telan-giectasia syndrome

Diseases of the Exocrine Pancreas

Any disease process affecting the pancreas may involve the islets and duce diabetes (table 1) May we recall the fibrocalculous pancreatopathy, thatoccurs in India, Africa and West Indies with a frequency similar to that of type

pro-2 diabetes This form involves young people with malnutrition and pancreaticcalculi, and is characterized by severe hyperglycemia and insulin dependencebut not by proneness to ketosis, as a moderate insulin secretion is retained

Gestational Diabetes mellitus (GDM)

GDM is defined as any degree of glucose intolerance with onset duringpregnancy It should be distinguished by the mild deterioration of glucose toler-ance which may occur also during normal pregnancy (particularly in the 3rdtrimester) The prevalence of GDM can range from 2 to 3% of pregnancies,depending on the different racial/ethnic subpopulations studied A known dia-betic woman who becomes pregnant is not classified as GDM The GDM is aserious problem and its recognition is important to prevent the associated peri-natal morbidity or mortality and the maternal complications (cesarean deliveryand chronic hypertension) GDM usually returns to a normal glucose tolerancestate after delivery, but 60% of affected women can develop diabetes within 15