**5. Importance of genetics for the clinician**

In the last 15 to 20 years, clinicians have been concerned with grasping the increasing complexity of this disease, with a gradual worldwide increase of its prevalence that has turned it into a pandemic disease. The latest evidence shows that, despite correcting their lifestyle, we cannot always achieve good metabolic control in patients in complex clinical situations.

There is a population, which is probably formed by most of our patients, with clinical features where their phenotype is a good reflection of their genotype; but we are finding with increasingly frequency clinical cases that are difficulty to classify with the current criteria.

In these cases, a high percentage of patients had severe difficulties with their metabolic control. It is precisely here where we need to carry out a proper genetic diagnosis, and eventually an immunologic one, to allow us a broader view of their pathology. Several clinical observations and systematic studies have shown that classical type 1 diabetes, whether in children, late onset in adults, or individuals over 65, can coexist in the same individual with "classic" type 2 diabetes where insulin secretion deficiency and insulin resistance are detected simultaneously (Serrano Rios, 2009). This group of patients is usually referred to a diabetes specialist because the primary care physician cannot decide about or control them. Once reached this stage and after correcting the variables that affect proper metabolic control, such as nutritional plan and regular physical activity, we can see that many of these patients keep having a poor metabolic control. These patients are usually overweight and / or obese with a very erratic response to anti-diabetic drugs alone or in combination, both between them and with insulin.

Complying with the algorithms, we almost always end up giving insulin to our patients, but in many cases this is probably done too late. This was analyzed by many authors that described as final: "therapeutic inertia". They are usually described as patients with a poor adherence to the treatment plan. Also, on average they start insulin treatment before the classical diabetes type 2 patients.

Thus, we are planning to deepen into genetic typing, in order to see if it may help us to understand the etiopathogenesis of these patients, and why they do not have the expected response to the drug treatment.

As stated above, these patients surprisingly had a genotype that does not agree with their phenotype. This was what allowed us as clinicians to begin to understand these facts and to find an explanation (albeit partial) of the poor outcome of each patient.

What are the issues that the clinician should consider for further study of certain patients?


In the last 15 to 20 years, clinicians have been concerned with grasping the increasing complexity of this disease, with a gradual worldwide increase of its prevalence that has turned it into a pandemic disease. The latest evidence shows that, despite correcting their lifestyle, we cannot always achieve good metabolic control in patients in complex

There is a population, which is probably formed by most of our patients, with clinical features where their phenotype is a good reflection of their genotype; but we are finding with increasingly frequency clinical cases that are difficulty to classify with the current

In these cases, a high percentage of patients had severe difficulties with their metabolic control. It is precisely here where we need to carry out a proper genetic diagnosis, and eventually an immunologic one, to allow us a broader view of their pathology. Several clinical observations and systematic studies have shown that classical type 1 diabetes, whether in children, late onset in adults, or individuals over 65, can coexist in the same individual with "classic" type 2 diabetes where insulin secretion deficiency and insulin resistance are detected simultaneously (Serrano Rios, 2009). This group of patients is usually referred to a diabetes specialist because the primary care physician cannot decide about or control them. Once reached this stage and after correcting the variables that affect proper metabolic control, such as nutritional plan and regular physical activity, we can see that many of these patients keep having a poor metabolic control. These patients are usually overweight and / or obese with a very erratic response to anti-diabetic drugs alone or in

Complying with the algorithms, we almost always end up giving insulin to our patients, but in many cases this is probably done too late. This was analyzed by many authors that described as final: "therapeutic inertia". They are usually described as patients with a poor adherence to the treatment plan. Also, on average they start insulin treatment before the

Thus, we are planning to deepen into genetic typing, in order to see if it may help us to understand the etiopathogenesis of these patients, and why they do not have the expected

As stated above, these patients surprisingly had a genotype that does not agree with their phenotype. This was what allowed us as clinicians to begin to understand these facts and to

What are the issues that the clinician should consider for further study of certain patients? a. Obese patients showing good response to insulin during intercurrence: many of these patients had an intercurrent disease, and with the temporary insulin treatment they achieved a good control (especially in early stages of diagnosis) that may be explained by an improvement in glucotoxicity and / or moderate insulinopenia. In these patients the insulin will be removed based on these myths: (1) Insulin is "ineffective"; (2) Insulin injection increases cardiovascular diseases and hyperinsulinemia; and (3) Insulin causes weight gain. The reluctance we see in these patients insulin is based on misguided or questionable in view of the genetic results

b. Poor response to insulin sensitizers: in particular thiazolidinedione but also biguanides. c. Poor response to secretagogues: it is usually attributed to glucotoxicity, but how much

find an explanation (albeit partial) of the poor outcome of each patient.

we are finding and the matching clinical trials.

influence does drug response have?

**5. Importance of genetics for the clinician** 

combination, both between them and with insulin.

classical diabetes type 2 patients.

response to the drug treatment.

clinical situations.

criteria.


Already, Nolan and Murphy (2001) posed an approach to the phenotypic and metabolic characterization of insulin-resistant patients, impaired glucose tolerance, or type 2 diabetes, and the use of glutamic acid decarboxylase antibodies (GADA), genetic markers, and models to estimate the insulin-resistance should be considered. These authors discuss the utility of using genetic markers based on population studies for type 2 diabetes mellitus. In what it has to do with the poor response to treatment, we must remember that both therapeutic inefficiency and drug toxicity, which have been seen in some individuals, have been frequently observed. Due to the presence of some drug metabolizing enzymes, drugs can participate as inhibitors or inducers of these enzymes, thereby their variation in activity between individuals. This variability in enzyme activity may reflect the existence of mutations in their genes.

#### **6. Conclusion: What is happening?**

The above mentioned points will lead us to review the different mechanisms that may have taken place in the evolutionary processes leading to the current status of this disease. We will consider some possible situations.

a. Researchers are considering the way natural selection is currently operating in humans. The concept of "the survival of the strongest individual" perhaps is no longer valid in the 21st century. Quintana Murci et al. (2007), at the Pasteur Institute (Paris), have looked for answers regarding the mechanisms of human evolution by comparing whole genomes of different populations. They analyzed more than 2.8 million genetic markers in different populations from different ethnic groups collected in the HAPMAP project. They found that 582 genes were subject to "strong selective pressures" during the last 60,000 to 10,000 years. Some of these genes are strongly associated to external features (e.g.: hair, skin color); others are to the response to pathogenic agents or drugs; and others to diseases with different incidences between populations, like diabetes, obesity, or hypertension. Barreiro pointed out that "it is the first time that it can be demonstrated, concerning the whole genome that natural selection participates in the differentiation of the populations" This work is not only useful to satisfy our curiosity, but also to aid in the identification of genes implied in different diseases (Barreiro et al., 2005; 2008).

Well defined since the XV century, clinical knowledge on diabetes gradually increased, and in the end two major distinct types of this pathology were described (1 and 2). In order to understand the current increase of chronic diseases, it is necessary to consider the important relationship between human feeding and human evolution. The regular offer of food that seemed to help human evolution so greatly in the past is also generating a great amount of diseases and their corresponding incapacities (like hemiplegics, aphasia, amputations, etc.). This fact is a true evolutionary paradox (Insua & Fuks, 2003).

Initially, we must consider the importance of the neutralization of positive selective pressure introduced by the availability of nutrients as consequence of human civilization. A good

Diabetes Type 1 and 2: What is Behind a Classification? 297

the lack of information, or misinterpretation, of the importance of the genetic components of the disease. But this disregarding could be considered also as having iatrogenic elements: we improve the current patient's quality of life, but on the other hand we hamper that of future persons. This process implies the emergence of currently unknown entities. New discoveries have allowed life extension for affected people, with the subsequent appearance of new pathological complications that were not seen before simply because affected

b. Are we witnessing a new type of diabetes, called "double o hybrid" by some authors? We believe that the phenomenon we are watching is simply another expression of the multifactorial nature of this disease. When we analyze populations with an ethnic mixture or of different ethnic origins, we begin to get a glimpse of the products of genetic admixture. This leads us to find a higher proportion of problematic patients that are difficult to classify because, when examining their phenotype, they are affected by certain genes that are masked by others. Hence, we can see families where, according to traditional classification, both entities (type 1 and type 2) coexist. This fusion would be associated with a new and intermediate phenotype (Tuomi, 2005). There are a few studies identifying patients where both type of diabetes overlap (Libman &. Becker, 2003; Pozzilli & Guglielmi, 2009); moreover, Pozzilli and Gugliemi (2007) place this entity in the middle of the double "rainbow" (made up of type 1 and type 2 diabetes). The "accelerator hypothesis" is a theory that shares this vision. It is a singular, unifying concept, which states that type 1 and type 2 diabetes are the same insulin-resistance disorder set against different genetic backgrounds. This hypothesis does not deny the role of autoimmunity, only its primacy in the process. It distinguishes type 1 and 2 diabetes only by tempo, the faster tempo reflecting the (inevitably) earlier presentation in the more

Recognition that susceptibility arises through the combination of multiple genetic pathways influencing hazardous factors in a nonlinear manner suggests that a 'decanalization' process contributes to the epidemic nature of common genetic diseases. The evolution of the human genome, combined with a marked environmental and cultural perturbation in the past two generations, might lead to the uncovering of cryptic genetic variations that are a major

This would be also favored by others processes such as an increase of life expectancy and fertility of affected individuals, the globalization phenomena, and increased admixture of different ethnic groups when compared with the past. The last phenomenon is clearly seen

Regardless of all the arguments presented in this chapter, we think that it is extremely important to introduce the genetic risk profile into the present diabetes classification criteria. This will clearly improve our capability of distinguishing between different types of

The effects of genetic traits in diabetes had been studied for decades, but few consistent risk factors have been well established. Currently, most of large scale studies on candidate genes do not combine the analysis of both types of diabetes. Establishing the association between genotype and phenotype would allow a deeper insight into the pathogenesis of the disease. Screening of associated anomalies and the possibility of anticipating future outcomes would

While for many countries, especially in Latin-America, individual genetic diagnosis can be very expensive to implement, we must realize that we are facing a multifactorial disease.

in Latin America and mainly in the Uruguayan population as it was stated above.

individuals passed away before their onset.

susceptible genotype (Wilkin, 2009).

diabetes or specific presentations.

be consequently improved.

source of disease susceptibility (Gibson, 2009).

example of the relationship between nutritional factors, diabetes, and population genetics is Szathmary's hypothesis (Marrodán, 2000) for explaining the high incidence of diabetes in several Amerindian populations (USA and Canada), either in reservations or in those adapted to western life.

Diabetes is a genetic-based disease whose manifestation is partly favored by excessive carbohydrate consumption. Possibly, several individuals with a specific genotype would produce insulin faster when faced with higher glucose levels than others; and they would also store this glucose as glycogen or fat more efficiently. This genotype would have been positively selected in a nutritional environment where periods of abundant or shortage of foods oscillate in a critical form. But this capacity for a faster answer to carbohydrate stimulus has a biological cost when food intake is constant. Under this situation, genes increasing insulin production are no longer beneficial to the individual because their carriers become obese, exhausting the physiological capacity of the pancreas, and leading to the subsequent development of diabetes (Marrodán, 2000; Harris, 2002). Variations in diabetes or obesity genes imply that adaptation to fasting was also an important selective agent. Quintana-Murci et al. (2007) pointed out that insulin-regulating genes have been positively selected. Thus, for instance, the ENPP1 gene has a mutation protecting against obesity and type II diabetes. This variant is present in 90% of non-African individuals and it is almost absent in African ones.

The susceptible genotype may have been selected in these populations because unusually frequent fasting periods may have taken place during the initial colonization of 'new worlds'. The abovementioned non-insulin dependent diabetes mellitus has shown a strong genetic component that may include a 'thrifty' genotype(s) (Neel 1962; Zimmet et al., 1990).

The 'thrifty' genotype(s) may have once allowed founding populations to survive both 'feast' and 'famine' conditions for several generations. Individuals carrying these genes would have had an increased efficiency for energy extraction (nutrition) from environmental scarce resources. During times of abundance those individuals with this predisposition would store more energy than those lacking it. When the progress of human civilization assured continuous fat-rich and fiber-poor diets, and a sedentary lifestyle, the 'thrifty' genotype(s) became disadvantageous, leading to obesity, increased insulin resistance, beta cell misbalance, and finally diabetes (Wendorf, 1991; 1992).

What was a selective advantage in past environments is currently, for most people in industrialized countries, an undesired condition. The result is obesity, diabetes, and the metabolic syndrome. For many years, diabetes was considered as a lethal or near-fatal disease by death simply by complications or by difficulties in the reproductive stages, both for men and women. More recently —the use of insulin is a landmark in this subject reproductive problems and some of their related complications have been solved.

In conclusion, evolutionary or Darwinian medicine considers that many contemporary diseases are associated to incompatibility between current human lifestyles and environments, and those under which human biology was shaped. As the observed difference between the incremental rates of both civilization and evolution is so great, most human evolutionary changes took place when our ancestors were gatherer-hunters. Thus, many characteristics and conducts that had adaptive value in the past may currently have non-adaptive value. Medicine has always tried to improve and look for the patient's cure. It really improved people's health, but in this process populational issues that are beyond the epidemiologic point of view were overlooked. This medical conduct may be explained by

example of the relationship between nutritional factors, diabetes, and population genetics is Szathmary's hypothesis (Marrodán, 2000) for explaining the high incidence of diabetes in several Amerindian populations (USA and Canada), either in reservations or in those

Diabetes is a genetic-based disease whose manifestation is partly favored by excessive carbohydrate consumption. Possibly, several individuals with a specific genotype would produce insulin faster when faced with higher glucose levels than others; and they would also store this glucose as glycogen or fat more efficiently. This genotype would have been positively selected in a nutritional environment where periods of abundant or shortage of foods oscillate in a critical form. But this capacity for a faster answer to carbohydrate stimulus has a biological cost when food intake is constant. Under this situation, genes increasing insulin production are no longer beneficial to the individual because their carriers become obese, exhausting the physiological capacity of the pancreas, and leading to the subsequent development of diabetes (Marrodán, 2000; Harris, 2002). Variations in diabetes or obesity genes imply that adaptation to fasting was also an important selective agent. Quintana-Murci et al. (2007) pointed out that insulin-regulating genes have been positively selected. Thus, for instance, the ENPP1 gene has a mutation protecting against obesity and type II diabetes. This variant is present in 90% of non-African individuals and it is almost

The susceptible genotype may have been selected in these populations because unusually frequent fasting periods may have taken place during the initial colonization of 'new worlds'. The abovementioned non-insulin dependent diabetes mellitus has shown a strong genetic component that may include a 'thrifty' genotype(s) (Neel 1962; Zimmet et al., 1990). The 'thrifty' genotype(s) may have once allowed founding populations to survive both 'feast' and 'famine' conditions for several generations. Individuals carrying these genes would have had an increased efficiency for energy extraction (nutrition) from environmental scarce resources. During times of abundance those individuals with this predisposition would store more energy than those lacking it. When the progress of human civilization assured continuous fat-rich and fiber-poor diets, and a sedentary lifestyle, the 'thrifty' genotype(s) became disadvantageous, leading to obesity, increased insulin resistance, beta cell

What was a selective advantage in past environments is currently, for most people in industrialized countries, an undesired condition. The result is obesity, diabetes, and the metabolic syndrome. For many years, diabetes was considered as a lethal or near-fatal disease by death simply by complications or by difficulties in the reproductive stages, both for men and women. More recently —the use of insulin is a landmark in this subject—

In conclusion, evolutionary or Darwinian medicine considers that many contemporary diseases are associated to incompatibility between current human lifestyles and environments, and those under which human biology was shaped. As the observed difference between the incremental rates of both civilization and evolution is so great, most human evolutionary changes took place when our ancestors were gatherer-hunters. Thus, many characteristics and conducts that had adaptive value in the past may currently have non-adaptive value. Medicine has always tried to improve and look for the patient's cure. It really improved people's health, but in this process populational issues that are beyond the epidemiologic point of view were overlooked. This medical conduct may be explained by

reproductive problems and some of their related complications have been solved.

adapted to western life.

absent in African ones.

misbalance, and finally diabetes (Wendorf, 1991; 1992).

the lack of information, or misinterpretation, of the importance of the genetic components of the disease. But this disregarding could be considered also as having iatrogenic elements: we improve the current patient's quality of life, but on the other hand we hamper that of future persons. This process implies the emergence of currently unknown entities. New discoveries have allowed life extension for affected people, with the subsequent appearance of new pathological complications that were not seen before simply because affected individuals passed away before their onset.

b. Are we witnessing a new type of diabetes, called "double o hybrid" by some authors? We believe that the phenomenon we are watching is simply another expression of the multifactorial nature of this disease. When we analyze populations with an ethnic mixture or of different ethnic origins, we begin to get a glimpse of the products of genetic admixture. This leads us to find a higher proportion of problematic patients that are difficult to classify because, when examining their phenotype, they are affected by certain genes that are masked by others. Hence, we can see families where, according to traditional classification, both entities (type 1 and type 2) coexist. This fusion would be associated with a new and intermediate phenotype (Tuomi, 2005). There are a few studies identifying patients where both type of diabetes overlap (Libman &. Becker, 2003; Pozzilli & Guglielmi, 2009); moreover, Pozzilli and Gugliemi (2007) place this entity in the middle of the double "rainbow" (made up of type 1 and type 2 diabetes).

The "accelerator hypothesis" is a theory that shares this vision. It is a singular, unifying concept, which states that type 1 and type 2 diabetes are the same insulin-resistance disorder set against different genetic backgrounds. This hypothesis does not deny the role of autoimmunity, only its primacy in the process. It distinguishes type 1 and 2 diabetes only by tempo, the faster tempo reflecting the (inevitably) earlier presentation in the more susceptible genotype (Wilkin, 2009).

Recognition that susceptibility arises through the combination of multiple genetic pathways influencing hazardous factors in a nonlinear manner suggests that a 'decanalization' process contributes to the epidemic nature of common genetic diseases. The evolution of the human genome, combined with a marked environmental and cultural perturbation in the past two generations, might lead to the uncovering of cryptic genetic variations that are a major source of disease susceptibility (Gibson, 2009).

This would be also favored by others processes such as an increase of life expectancy and fertility of affected individuals, the globalization phenomena, and increased admixture of different ethnic groups when compared with the past. The last phenomenon is clearly seen in Latin America and mainly in the Uruguayan population as it was stated above.

Regardless of all the arguments presented in this chapter, we think that it is extremely important to introduce the genetic risk profile into the present diabetes classification criteria. This will clearly improve our capability of distinguishing between different types of diabetes or specific presentations.

The effects of genetic traits in diabetes had been studied for decades, but few consistent risk factors have been well established. Currently, most of large scale studies on candidate genes do not combine the analysis of both types of diabetes. Establishing the association between genotype and phenotype would allow a deeper insight into the pathogenesis of the disease. Screening of associated anomalies and the possibility of anticipating future outcomes would be consequently improved.

While for many countries, especially in Latin-America, individual genetic diagnosis can be very expensive to implement, we must realize that we are facing a multifactorial disease.

Diabetes Type 1 and 2: What is Behind a Classification? 299

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#### **7. Acknowledgment**

This chapter could not have been written without the valuable collaboration of graduate and postgraduate students that are part of our research group (in alphabetic list): Br. Matías Fabregat, B.S. Joaquina Farías, MSc. Mariana Fernández, B.S. Ana Laura Reyes, Br. Jorge Souto, MSc. Pilar Zorrilla.

#### **8. References**


Thus, although classifications may be useful, they only have relative value. We must keep an open mind to the fact that there are patients that do not fall in any of them, and we must remember that genetics is at the base of diabetes, as there are multiple genes that interact both with the environment and between them. These interactions can result in a somewhat "liar" phenotype. In the preceding sections we saw how mutations in a few genes associated to insulin resistance may mask the presence and/or action of genes causing autoimmune disorders. Moreover, if we take into account the modifications observed with genome scanning, where there are millions of Single Nucleotide Polymorphisms, it is virtually

Although we are aware that understanding the pathogenesis of hyperglycemia or the basis for an effective treatment may be deemed as more important than knowing the type of diabetes we are dealing with, we are currently persuaded that the distinguishing between different types or presentation forms of diabetes based on genetic information is an

This chapter could not have been written without the valuable collaboration of graduate and postgraduate students that are part of our research group (in alphabetic list): Br. Matías Fabregat, B.S. Joaquina Farías, MSc. Mariana Fernández, B.S. Ana Laura Reyes, Br. Jorge

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**7. Acknowledgment** 

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**15** 

*Italy* 

**The Enlarging List of Phenotypic** 

 **Clinical Identification of Families** 

**at Risk for Type 1 Diabetes** 

Elena Matteucci and Ottavio Giampietro *Department of Internal Medicine, University of Pisa* 

**Characteristics That Might Allow the** 

Type 1 diabetes is a chronic metabolic disease whose aetiology and pathogenesis remain not completely understood. Current criteria for the diagnosis of diabetes are: 1) haemoglobin A1c ≥ 6.5% (assayed using a method that is certified by the National Glycohemoglobin Standardization Program, NGSP, and standardised or traceable to the Diabetes Control and Complications Trial, DCCT, reference assay), 2) fasting plasma glucose (FPG) ≥ 126 mg/dl, 3) 2-hour plasma glucose ≥ 200 mg/dl during an oral glucose tolerance test (OGTT, 75 g), 4) a random plasma glucose ≥ 200 mg/dl (American Diabetes Association, 2011). The classification of diabetes includes: type 1 diabetes, type 2 diabetes, other specific types of diabetes due to other causes, and gestational diabetes mellitus. Type 2 diabetes, which is usually associated with obesity and older age, results from insulin resistance and progressive failure of pancreatic beta-cell function. Type 1 diabetes, which has usually an abrupt onset in younger people, is an organ-specific autoimmune disease characterised by absolute insulin deficiency resulting from beta-cell destruction. However, autoimmunity may not be the primary cause: environmental triggers are believed to precipitate type 1 diabetes in genetically susceptible individuals (van Belle et al., 2011). The overall incidence of type 1 diabetes is increasing; the majority of the increase is observed in the youngest age group, which also appeared to be the heaviest (Evertsen et al., 2009). Indeed, the accelerator hypothesis (Wilkin, 2009) suggests that type 1 and type 2 diabetes are the same disorder of insulin resistance set against different genetic backgrounds. Three processes could variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance, and autoimmunity. None of these accelerators leads to diabetes without excess weight, which causes an increase in insulin resistance and, thus, the weakening of glucose control. In turn, the glucotoxicity accelerates beta-cell apoptosis directly and by inducing beta-cell immunogens and autoimmunity in genetically predisposed subjects. Insulitis is commonly observed in recent-onset type 1 diabetes, but it does not uniformly affect all insulincontaining islets (differences in islet function?). It has been suggested that under increased insulin demand (puberty, adolescence, high sugar intake, etc.) a population of islets may be more prone to dysfunction or death, thereby attracting antigen presenting cells and

**1. Introduction** 

Noviembre

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