**2. Historical evocation**

Diabetes was known some millenniums before the Christian era, and it was in India where the disease was more deeply studied during the ancient age. The first data come from the *Ayurveda,* texts concerning medicine writings (sankrit texts). The word *Ayurveda* means knowledge or "science life"; it has profound roots on the philosophy and Hinduistic spirituality; it was developed between years 3000 and 500 b.C. on the valley rivers of the Indian civilization. Its knowledge was transmitted orally from generation to generation through the verses known as *vedas*. At that time some documents showed detailed information about unquenchable thirst –polydipsia-in the diabetic patients, increased urine –polyuria-, and sugar in urine –glycosu‐ ria-. Instead of sweetened and viscous consistency of the urine, they described other symptoms such as halitosis, digestive and respiratory disorders, somnolence, tuberculosis, and foruncu‐ losis. The autochthonous black ants indirectly helped to detect this pathology. The physicians observed how ants and flies congregated around the urine being attracted by its taste. Based on that circumstance, it was called honey urine. Also, they pointed out that diabetes were more frequent in obese people, usually taking rice and sweeten food.

The majority of historians accept the papyrus form of 1862 close to the ruins of Luxor, the ancient sacred city of Thebes. The well-known document, a roll of papyrus by two meters long and thirty centimeters large, is a vast compendium with the totality of knowledge at the pharaohs era like at current texts of medicine. The physician-priest recommended, as treat‐ ment, fatty of calf, beer, leaf of mint, hippopotamus's blood and offering sacrifice to gods. The antiquity of this document is about 3500 years; it was acquired and analyzed by the German Egyptologist George M. Ebers (1837-1898). It is currently kept in good conditions at the library of the University of Leipzig. The first description of diabetes appeared in this papyrus where polyuria was described. Celsus in the 1st century of our era established from his personal experience the "painless polyuria with dangerous emaciation". Areteus of Capadocia (century II), a Greek physician named the disease *diabetes;* in greek, *diabainein* means "to pass through", or "running throw" which is in relation to severe diuresis favourable to final outcome; and from Latin, *mellitus* (sweetened with honey). Claudius *Galenus*(3rdcentury) considered diabetes as a kidney disease. Thomas Willis (1621-1675) in 1675 found in the patients the sweetness of the urine, and William Cullen (1710-1790) proposed the term *mellitus*. The hereditary character of the disease was postulated by R. Morton in his text *Phthisiologia* (1689). Another historical event was made by P. Langerhans (1847-1888) when he described the pancreatic islets. Allen (1914) with an uniqueness criteria considered diabetes as a hereditary disorder of carbohydrate metabolism resulting in insufficient production of insulin. Since the discovery of insulin by Frederick Grant Banting, Charles Herbert Best and John Richard MacLeod, Nobel Prizes of Medicine in 1923, the prognosis of the disease is improving, although the *prevalence* still rises progressively from 5 % at age 20 to older people > 75 years.

On the other hand, insulin is a polypeptide hormone synthesized in the beta cells of the islets of Langerhans of the endocrine pancreas, and it is necessary for normal metabolization of glucose by most cells of the body. In diabetic persons the capacity of body cells to use glucose is inhibited, thereby increasing blood sugar levels (hyperglycemia). When high levels of glucose are present in the blood, the excess must be excreted in the urine (glycosuria). The symptoms derived from the disease are increased urinary volume, thirst, itching, hunger, weight loss, and weakness; in medical expression the classical findings are well known:

Diabetes affects an estimate of 366 million people worldwide, with type 2 diabetes mellitus (T2DM) accounting for more than 90% of the cases. Renal insufficiency is a common comor‐ bidity condition in T2DM patients with chronic kidney disease (CKD,) defined as kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 for > 3 months. The kidney is both the origin and victim of elevated blood pressure. Hypertension is a pathogenic factor that contributes to the deterioration of kidney function. Therefore, manage‐ ment of hypertension (salt reduction intake adequate diet, exercise and antihypertensive drugs) has become the most important intervention control all modalities of chronic kidney disease (CKD). The role of hypertension in renal disease is crucial. The aged world population is increasing. The ageing is the most common risk factor for the development of hypertension

Diabetes was known some millenniums before the Christian era, and it was in India where the disease was more deeply studied during the ancient age. The first data come from the *Ayurveda,* texts concerning medicine writings (sankrit texts). The word *Ayurveda* means knowledge or "science life"; it has profound roots on the philosophy and Hinduistic spirituality; it was developed between years 3000 and 500 b.C. on the valley rivers of the Indian civilization. Its knowledge was transmitted orally from generation to generation through the verses known as *vedas*. At that time some documents showed detailed information about unquenchable thirst –polydipsia-in the diabetic patients, increased urine –polyuria-, and sugar in urine –glycosu‐ ria-. Instead of sweetened and viscous consistency of the urine, they described other symptoms such as halitosis, digestive and respiratory disorders, somnolence, tuberculosis, and foruncu‐ losis. The autochthonous black ants indirectly helped to detect this pathology. The physicians observed how ants and flies congregated around the urine being attracted by its taste. Based on that circumstance, it was called honey urine. Also, they pointed out that diabetes were more

The majority of historians accept the papyrus form of 1862 close to the ruins of Luxor, the ancient sacred city of Thebes. The well-known document, a roll of papyrus by two meters long and thirty centimeters large, is a vast compendium with the totality of knowledge at the pharaohs era like at current texts of medicine. The physician-priest recommended, as treat‐ ment, fatty of calf, beer, leaf of mint, hippopotamus's blood and offering sacrifice to gods. The

polyuria, polydipsia, polyphagia, slimming, and asthenia [2, 3].

frequent in obese people, usually taking rice and sweeten food.

and diabetes, as well as CKD [4].

**2. Historical evocation**

120 Treatment of Type 2 Diabetes

The Canadian physiologist Frederick Grant Banting (1891-1941) and the medical student Charles Herbert Best (1899-1978) isolated insulin in Toronto in 1922. At that point, the new era on the treatment of diabetes was started. The results of the work by the German internist Oskar Minkowski (1858-1931) and Joseph von Mering (1894-1908) of removing the pancreas, led to the conclusion that the cause of diabetes resides in the lack of internal secretion of the Lan‐ gerhans's islets placed in the pancreas.

Many researchers have dedicated their efforts to obtain the hormone against diabetes. In 1909, the Belgian Jean de Meyer named *insulin* the substance produced by the islets of Langerhans. Particularly, the internist Georg Ludwig Zülzer (1870-1949) was able to isolate after 1903 an effective compound. Nevertheless, two circumstances led him to abandon his work: a) uncontrollable toxic allergic reactions; and, b) overdose impossible to recognize for the absence of method of blood glucose determination. On July, 1921, the director of the Physiology Institute of Toronto, John James Richard MacLeod (1876-1935) provided to the young physician Frederick Grant Banting with a laboratory and ten dogs, and 21-year-old *student* Charles Herbert Best as his assistant. Banting and Best had been working to obtain insulin from a saline solution of triturated islets of pancreas. The extract was administered to diabetic dogs, by intravenous injection; simultaneously Best carried out continuous determinations of sugar in blood. This work made possible the new measuring methods that need only 0.2 ml of blood instead of 25 ml. After this finding Banting and Best studied better and easier procedures to obtain the hormone from cow fetus of four months. They discovered that the active substance was better extracted with acetone instead of acidulous alcohol. The decisive experiments were carried out between the 7 and 14th August of 1921.

After the first and successful achievements, MacLeod decided to interrupt any other investi‐ gation and focus on the insulin project: purification, control and manufacturing. The chemist James Bertram Collip (1892-1965) was able to obtain huge amounts of insulin and to success to its standardization. The latter is of capital importance because overdose can produce muscle spasm due to hypoglycemia.

Since the end of the 19thcentury, researchers have found the relationship between the pancreas and the metabolic disease –diabetes-. Some of them pointed out that the clinical problems are produced by the lack of a hormonal substance secreted by the endocrine pancreas or Langer‐ han's islets, although the German Oskar Minkowski (1858-1931) and others investigators failed to isolate this hormone. Edward Albert Sharpey-Schafer (1850-1935) coined the word "insulin"; he considered that insulin controls the hydrocarbonate metabolism and that the absence of insulin will be followed by hyperglycemia and an increase of glucose in urine. After that conclusion, pancreatic extract was given to diabetic patients; but unfortunately, this attempt was unsuccessful because the hormone was destroyed by the proteolytic enzymes. Also, the technical procedures for blood and urine glucose determinations available were rudimentary and with little accuracy. After numerous attempts, researchers obtained more purified insulin to be used in the clinical practice. Insulin was used for the first time in 1922 in a 14-year-old diabetic boy, who presented good results; it was the first publication concerning the efficacy of insulin in humans and was published in the prestigious journal *Canadian Medical Association Journal*.

One year later, in 1923, the Medicine Nobel Prize was awarded to Banting and MacLeod for his crucial medical milestone. In 1926, Jakob Abel found the synthesis of insulin; this finding was published in the *Proceedings of the National Academy of Sciences*, Washington, with the article entitled *Crystalline insulin*. After that, the era of insulin was started.

As it is well known, there are two modalities of the disease: insulin dependent diabetes mellitus or IDDM (type I) found in young people requiring daily insulin injection; although most cases of IDDM appear before age 20, the disease can develop late in life. In these patients, the necessary insulin is not secreted by the pancreas and hence must be managed by parenteral way. On the other hand, Type II, non-insulin dependent diabetes mellitus (NIDDM), adult onset diabetes, can be controlled by strict dietary restriction of carbohydrates, oral hypogly‐ cemic agents (blood-sugar-lowering) and also insulin in some particular patients. The situation coming from sluggish pancreatic insulin secretion and concomitant tissue resistance to secreted insulin worsens insulin secretion by the beta cells. Anyway, despite the previous classification as juvenile or adult diabetes, either type can be observed at any age; however, NIDDM is the most common clinical presentation found in up to 90 percent of all forms of diabetes. The risk factors predisponing to type 2 diabetes are pointed out in table 1.

From the clinical point of view, to get a suitable control of the disease (blood glucose, glycated hemoglobin, lipids profile, body weight, and quality of life) it is crucial to ensure successful outcomes [table 2]. We must realize that subjects with asymptomatic, undiagnosed diabetes not unusually develop serious complications. Despite the absence of fasting hyperglycemia large-scale screening with glucose tolerance test should be established in many cases. Nowa‐ days, the goals of therapy with insulin or oral agents for varied circumstances is frequently hazardous [5]. This particular point explains the urgent necessity to find better drugs (more effective and well tolerated). The way to reach this goal is, undoubtedly, the *clinical investiga‐ tion*; in others words, *clinical trials* [6].

Family antecedents of diabetes (parents)

Obesity (Body Mass Index BMI >25 kg/m2

Sedentarism

to its standardization. The latter is of capital importance because overdose can produce muscle

Since the end of the 19thcentury, researchers have found the relationship between the pancreas and the metabolic disease –diabetes-. Some of them pointed out that the clinical problems are produced by the lack of a hormonal substance secreted by the endocrine pancreas or Langer‐ han's islets, although the German Oskar Minkowski (1858-1931) and others investigators failed to isolate this hormone. Edward Albert Sharpey-Schafer (1850-1935) coined the word "insulin"; he considered that insulin controls the hydrocarbonate metabolism and that the absence of insulin will be followed by hyperglycemia and an increase of glucose in urine. After that conclusion, pancreatic extract was given to diabetic patients; but unfortunately, this attempt was unsuccessful because the hormone was destroyed by the proteolytic enzymes. Also, the technical procedures for blood and urine glucose determinations available were rudimentary and with little accuracy. After numerous attempts, researchers obtained more purified insulin to be used in the clinical practice. Insulin was used for the first time in 1922 in a 14-year-old diabetic boy, who presented good results; it was the first publication concerning the efficacy of insulin in humans and was published in the prestigious journal *Canadian Medical Association*

One year later, in 1923, the Medicine Nobel Prize was awarded to Banting and MacLeod for his crucial medical milestone. In 1926, Jakob Abel found the synthesis of insulin; this finding was published in the *Proceedings of the National Academy of Sciences*, Washington, with the article

As it is well known, there are two modalities of the disease: insulin dependent diabetes mellitus or IDDM (type I) found in young people requiring daily insulin injection; although most cases of IDDM appear before age 20, the disease can develop late in life. In these patients, the necessary insulin is not secreted by the pancreas and hence must be managed by parenteral way. On the other hand, Type II, non-insulin dependent diabetes mellitus (NIDDM), adult onset diabetes, can be controlled by strict dietary restriction of carbohydrates, oral hypogly‐ cemic agents (blood-sugar-lowering) and also insulin in some particular patients. The situation coming from sluggish pancreatic insulin secretion and concomitant tissue resistance to secreted insulin worsens insulin secretion by the beta cells. Anyway, despite the previous classification as juvenile or adult diabetes, either type can be observed at any age; however, NIDDM is the most common clinical presentation found in up to 90 percent of all forms of

diabetes. The risk factors predisponing to type 2 diabetes are pointed out in table 1.

From the clinical point of view, to get a suitable control of the disease (blood glucose, glycated hemoglobin, lipids profile, body weight, and quality of life) it is crucial to ensure successful outcomes [table 2]. We must realize that subjects with asymptomatic, undiagnosed diabetes not unusually develop serious complications. Despite the absence of fasting hyperglycemia large-scale screening with glucose tolerance test should be established in many cases. Nowa‐ days, the goals of therapy with insulin or oral agents for varied circumstances is frequently hazardous [5]. This particular point explains the urgent necessity to find better drugs (more effective and well tolerated). The way to reach this goal is, undoubtedly, the *clinical investiga‐*

entitled *Crystalline insulin*. After that, the era of insulin was started.

*tion*; in others words, *clinical trials* [6].

spasm due to hypoglycemia.

122 Treatment of Type 2 Diabetes

*Journal*.

Race/ethnicity

Previously identified impaired fasting glucose (IFG), or impaired glucose tolerance (IGT)

Gravid diabetes mellitus (GDM)

HDL cholesterol < 35 mg/dl and/or triglyceride level > 250 mg/dl

Previous vascular disease

Acanthosis nigricans or polycistic ovary syndrome

**Table 1.** Risk factors predisposing to type 2 diabetes mellitus.

1. Symptoms of diabetes –polyuria, polyphagia, polydipsia, slimming or asthenia- plus random blood glucose level 200 mg/dl. Or

2. Fasting plasma glucose > 126 mg/ dl. Or

3. Two-hour plasma glucose (200 mg/dl) during an oral glucose tolerance test.

1) Random is considered at any time since the last meal

2) Fasting is defined as no food intake for previous 12 hours

3) Two-hours plasma glucose > 200 mg/dl during glucose tolerance test

**Table 2.** Clinical and laboratory criteria for diagnosis of diabetes mellitus

In 1912, two Boston researchers, F. G Benedict and Elliot P. Joslin, founder of the Joslin Diabetes Center –Boston-iniciated extensive metabolic balance studies in diabetic patients whose circulating blood glucose levels were high; they intended to control the disease by an strict dietary restriction of carbohydrates. And now, more than a century after the creation of the former institution, it continues the tradition of excellence recognized everywhere as a diabetes research, treatment, and teaching center. It is focused to improve the lives of persons with diabetes today and in the future. We now know that the excreted sugar coming from exogenous and endogenous proteins is converted in our body by the liver into glucose. But, in spite of the hard investigations, nowadays diabetes remains a difficult clinical problem mostly in the Western and developed countries.

### **3. Personal overview**

Based on this controversial clinical status and related to our conventional duty since March 1990, our group in Granada (Spain) has created a *Hypertension and Lipid Unit*, and during the large *interim* period (twenty four years) until now, we have carried out a huge work by participating in several international clinical studies –more than one hundred fifty-focused mostly on hypertension and diabetes, but also on lipid disorders and ischemic heart disease; many of them are well recognized everywhere by prestigious publications using acronyms titles for an easier identification of them: SYST-EUR, HYVET, CONVINCE, VALUE, ONTAR‐ GET, TRANSCEND, TECOS, STABILITY, SAVOR, ODISSEY, OMNEON, LIXILAN, as well as other works in process and others scheduled to start in the near future.

Our participation in clinical trials about diabetes represents a big and continual effort in the most relevant clinical research of this important and crucial area. We believe and hope that the abstract's information (clinical and pedagogical) contained in this article will be suitable to many physicians (practitioners, internists, cardiologists, endocrinologists), chemists, nurses and others health professionals. Unfortunately, nowadays the knowledge concerning clinical trials and it relevance for research and health is very poor not only for physicians but also for the general population. We would like that the present book and particularly this chapter will offer some attractive and available information for a better knowledge of diabetes mellitus and current medical challenges.

From this particular contribution we present to the reader a conventional design of clinical trials commonly used everywhere. *Sensu lato*, the primary objective is to provide better benefits to diabetic patients by the new non commercialized drugs (phases II, III of clinical trials) matched to ordinary ones or placebo. To reach the aim of this research it is mandatory to have a huge financial support coming from pharmaceutical companies, with the indispensable contribution of investigators, patients, data managers, physicians, auxiliary staff, technical support, computer experts, nurses, etc. In summary, the following twenty items represents a schematic example common in many clinical trials in which we participated.
