The History and Clinical Presentation of Diabetes Mellitus

Diabetes mellitus (DM) refers to a group of common metabolic disorders which share the phenotype of hyperglycemia.19 There are several distinct types of DM which are caused by a complex interaction of genetics, environmental factors and lifestyle choices.20 With a worldwide increasing incidence, DM will likely to continue to be a leading cause of morbidity and mortality.21 Depending on the etiology of the DM, factors that contribute to hyperglycemia include reduced insulin secretion, decreased glucose utilization, and increased glucose production.22 The metabolic dysregulation which is associated with DM causes a variety of secondary pathophysiologic changes involving multiple organ systems that impose a tremendous burden on the individual with diabetes as well as the health care system.

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Historical Aspects

The description of diabetes was documented in the writings of Hindu scholars as early as in 1500 BC. They had already described “a mysterious disease-causing thirst, enormous urine output, and wasting away of the body with flies and ants attracted to the urine of people.

” The Greek Apollonius of Memphis probably first coined the term “diabetes” around 250 BC, which literally meant “to go through” or siphon as the disease drained more fluid than a person could consume. The Latin word “mellitus” was added later because it made the urine Department of General Medicine , SMCH, Silchar sweet. The sweet taste of diabetic urine was noted by the Indian physicians (Sushruta and Charaka) in the 5th and 6th century AD, who had termed it as ‘Madhu meha’ meaning passing urine resembling honey (Madhu). The term ‘Diabetes mellitus’, meaning an illusion to the honeyed taste of urine, was first used by John Rollo and others in the late 18th century, to distinguish it from other polyuric states in which urine was tasteless.

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The islet cells of pancreas were discovered by a young German medical student, Paul Langerhans. Sharpey-Shafer of Edinburgh, in 1916, suggested that a single chemical was missing from the pancreas of diabetic patients and proposed its name as “insulin.” The term insulin originates from the word “Insel”, which is German word for an islet or island. Researchers like E.L. Scott and Nikolae Paulesco were able to successfully extract insulin from the pancreas of experimental dogs. In 1921 the key breakthrough, though, came from the Toronto University with the discovery of insulin. In 1923, FG Banting and JJR Macleod were awarded the Nobel Prize for Physiology or Medicine.26 Banting and Best injected the crude pancreatic extract “thick brown muck” into a 14-year-old boy named “Leonard” in January 1922 and his blood sugar levels dropped significantly, but an abscess developed at the injection site making him acutely ill. A refined extract was again administered after 6 weeks, causing drop in blood sugar levels from 520 mg/dl to 120 mg/dl within 24 hours.

Major advances in the understanding of diabetes and metabolism have included:

A. The sequencing of insulin in 1955 by Frederick Sanger and elucidation of its three-dimensional structure in 1969 by Dorothy Hodgkin. B. The measurement of insulin concentration using the first radio immunoassay, by Solomon Berson and Rosalyn Yalow in 1959. C. The isolation of proinsulin in 1967 by Donald Steiner’s group. D. Identification of specific insulin receptors by Pierre Freychet and colleagues in 1971, and E. The sequencing of the insulin receptor in 1985.

Mile stones in the management of diabetes have included:

A. The development of long acting insulin preparations (isophane) in 1936 by Hans Christian Hagedorn and colleagues. B. The testing of sulfonylureas by Auguste Loubatieres in 1944. C. First therapeutic use of a biguanide (phenformin) by G. Ungar in 1957. D. Introduction in the late 1970’s of dry reagent test strips suitable for self-monitoring of blood glucose, and E. Definitive proof from the diabetes control and complications trial (DCCT) published in 1993, that strict glycemic control could slow or prevent the development of diabetic microvascular complications.28

Classification of Diabetes Mellitus

I. Type 1 diabetes: (beta cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. Idiopathic

II. Type 2 diabetes: (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance)

III. Other specific types of diabetes

A. Genetic defects of beta cell function characterized by mutations in:

1. Hepatocyte nuclear transcription factor(HNF) 4α (MODY 1)
2. Glucokinase (MODY 2) 3) HNF-1 α (MODY 3)
3. Insulin promoter factor-1 (IPF-1; MODY 4) 5) HNF-1 β (MODY 5)
4. NeuroD1 (MODY 6)
5. Mitochondrial DNA
6. Subunits of ATP-sensitive potassium channel
7. Proinsulin or insulin

B. Genetic defects in insulin action:

1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipodystrophy syndromes

C. Diseases of the exocrine pancreas: (pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibro calculous pancreatopathy, mutations in carboxyl ester lipase).

D. Endocrinopathies: (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma).

E. Chemical and drug induced: [glucocorticoids, vacor (a rodenticide), pentamidine, diazoxide, nicotinic acid, β- adrenergic agonists, thiazides, hydantoins, asparaginase, α- interferon, protease inhibitors, antipsychotics (atypicals and others), epinephrine]. F. Infections: (congenital rubella, coxsackievirus, cytomegalovirus)

G. Immune-mediated diabetes of uncommon forms: (anti-insulin receptor antibodies, “stiff-person” syndrome).

H. Other genetic syndromes associated with diabetes sometimes: (Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Wolfram’s syndrome, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome).

IV. Gestational diabetes mellitus (GDM)

Epidemiology

According to International Diabetes Federation estimates, around 415 million people had DM in 2015 and this number is expected to rise to 642 million by 2040.30 Although the prevalence of both type 1 and type 2 DM is increasing worldwide, the prevalence of type 2 DM is rising much more rapidly, presumably because of increasing obesity, reduced activity levels as countries become more industrialized, and the aging of the population. The countries with the greatest number of individuals with diabetes in 2013 are China (98.4 million), India (65.1 million), United States (24.4 million), Brazil (11.9 million), and the Russian Federation (10.9 million).31

Prevalence of Diabetes in India

India is home to 69.1 million people with DM and is estimated to have the second highest number of cases of DM in the world after China in 2015.30 The prevalence of DM in India ranges from 5–17%, with higher levels found in the southern part of the country and in urban areas.32-37

Indians have a peculiar genetic composition and Asian Indian phenotype that make them more susceptible to develop metabolic syndrome, diabetes mellitus and coronary artery disease. Indians characteristically have increased insulin resistance, greater abdominal adiposity (higher waist circumference despite lower body mass index), higher prevalence of impaired glucose tolerance, lower adiponectin and higher high sensitive C-reactive protein levels; contributing to a greater risk of developing disease at a relatively younger age.38,39

However, the rapid epidemiological transition associated with changes in dietary patterns and decreased physical activity seems to be the primary driver of the epidemic of diabetes, as evident from the higher prevalence of diabetes in the urban population. The prevalence of premature coronary artery disease is much higher in Indians compared to other ethnic groups, even though the prevalence of microvascular complications of diabetes like retinopathy and nephropathy are comparatively lower in Indians. The most disturbing trend is the shift in age of onset of diabetes from the elderly to a younger age in the recent years which can have long lasting adverse effects on nation’s health and economy.

Diagnosis of Diabetes

For decades, either the fasting plasma glucose (FPG) or the 2-hour value in the 75-gram oral glucose tolerance test (OGTT) were used for the diagnosis of diabetes .41 However, in 2009, the use of HBA1C was recommended for the diagnosis of diabetes, keeping 6.5% as threshold, by International Expert Committee that included representatives of the ADA, the International Diabetes Federation (IDF), and the European Association for the Study of Diabetes (EASD)42,, and this criterion was adopted by ADA in 2010. The National Glycohemoglobin Standardization Program (NGSP) certified method should be used for the diagnostic tests and it should also be standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. There are several advantages of using HBA1C over the FPG and OGTT, which includes greater convenience, since fasting is not required; evidence to suggest greater pre-analytical stability; and less day-to-day perturbations during periods of stress and illness. However, there are disadvantages which includes greater cost, the less availability of HBA1C testing in certain regions of the developing world, and the incomplete correlation between average glucose in certain individuals and HBA1C.

In addition, HBA1C levels can vary with patients’ ethnicity, with certain anemias and hemoglobinopathies.43 Patients having an abnormal hemoglobin but with normal red cell turnover, such as sickle cell trait, an HBA1C assay without the interference from abnormal hemoglobins should be used. For the diagnosis of diabetes in some special conditions like abnormal red cell turnover, such as pregnancy, recent blood loss or transfusion, or some anemias, the glucose criteria should be employed exclusively.

The established glucose criteria for the diagnosis of diabetes (FPG and 2-hour PG) still remains the same. There is no perfect concordance between HBA1C and either glucose-based test. Analyses of National Health and Nutrition Examination Survey (NHANES) data indicate that, assuming universal screening of the undiagnosed, one-third fewer cases of undiagnosed diabetes is detected by HBA1C with a cut-off point of 6.5% than with a fasting glucose cut point of 126 mg/dl (7.0 mmol/l).44

Criteria for Diagnosis of Diabetes

1. Symptoms of diabetes plus random blood glucose concentration ≥ 11.1mmol/L (200mg/dL) a or,

2. Fasting Plasma Glucose ≥ 7.0 mmol/L (126mg/dL) b or,

3. Hemoglobin A1C ≥ 6.5% c or,

4. 2-hour plasma glucose ≥ 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test.d

a) Random is defined as without regard to time since the last meal.

b) Fasting is defined as no caloric intake for at least 8 hours.

c) Hemoglobin A1C test should be performed in a laboratory using a method approved by the National Glycohemoglobin Standardization Program and correlated to the reference assay of the Diabetes Control and Complication Trial. Point-of-care hemoglobin A1C should not be used for diagnostic purpose.

d) The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, not recommended for routine clinical use.

These criteria should be confirmed by repeat testing on a different day if in the absence of unequivocal hyperglycemia and acute metabolic decompensation