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Dr KHALED MB.
About Type 2 Diabetes
Adapted from
F. Belfiore, S. Iannello
Introduction
Diabetes mellitus is likely to become one of the most prevalent and economically important diseases of the 21st century largely owing to an increasing incidence of type 2 diabetes mellitus (DM) in the developed nations and many of the developing nations. Every physician will encounter a patient who has diabetes. Multiple factors, both environmental and genetic, contribute to the pathogenesis of the disease. Type 2 DM is particularly common in obese sedentary populations, while type 1 DM can have a dramatic onset and be a major therapeutic challenge.
The world is witnessing an increase in new cases of diabetes, in both the developed and the developing nations, of near epidemic proportion. This ubiquitous condition will have an ever-increasing impact on all aspects of medicine and public health. It follows that all practicing physicians must seek to gain at least a basic knowledge and understanding of this important global health problem that is so closely linked to the increasing prevalence of obesity.
Diabetes is the paradigm of a condition that necessitates a multidisciplinary approach to its management and treatment. Primary care physicians, hospital physicians, surgeons, nurses, dieticians, psychologists, podiatrists and ophthalmologists are all drawn into this process. In addition, medical students and postgraduate doctors need to learn about diabetes and its protean manifestations.
Diabetes mellitus (DM) is set to become one of the world’s biggest health problems owing to the projected increase in new cases. The word diabetes means ‘to run through’ or ‘a siphon’ in Greek and the condition has been recognized since the time of the ancient Egyptians. Mellitus (from the Latin and Greek roots for ‘honey’) was later added to the name of this disorder when it became appreciated that diabetic urine tasted sweet.
The personal and public health costs of diabetes are high. It has been estimated that diabetes accounts for 2.8% of all hospital admissions in some countries.
Etiological Classification, Pathophysiology and Diagnosis
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,which are caused by a relative or absolute deficiency of insulin secretion 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 literature since 1979 and to decide the adequate changes in the classification and 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).
Definition and Description of Diabetes mellitus
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 ofdiabetes mellitus falls into two major forms: type 1 and type 2 diabetes.
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. The metabolic alterations are less pronounced than those in type 1 diabetes. 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 fromactivation of lipolysis and/or the often enhanced fat mass due to coexisting 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.
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Figure 1. Pathophysiology Mechanism of Diabetes
Table 1. Etiologic classification of diabetes mellitus
1. Type 1 diabetes A. Immune-mediated 2. Type 2 diabetes 3. Other specific types A. Genetic defects of b-cell function(MODY-1,MODY-2,MODY-3, mitochondrialDNA, and others) B. Genetic defects in insulin action (typeAinsulin resistance, leprechaunism,Rabson-Mendenhall syndrome, lipoatrophic diabetes, and others) C. Diseases of the exocrine pancreas (pancreatitis, pancreatectomy, trauma, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, and others) D. Endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma, and others) E. Drug- or chemical-induced diabetes (vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, b-adrenergic agonists, thiazides, dilantin, a-interferon, and others) F. Infections (congenital rubella, cytomegalovirus, and others) G. Uncommon forms of immune-mediated diabetes (‘stiff-man’ syndrome, anti-insulin receptor antibodies, and others) H. Other genetic syndromes sometimes associated with diabetes (Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Wolfram’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Lawrence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome, and others) 4. Gestational diabetes mellitus (GDM) |
Comment.
Diagnostic Criteria for Diabetes mellitus
A precocious diagnosis of diabetes is important to prevent or attenuate late diabetic complication, and depends upon the adequate use and interpretation of laboratory tests (especially in absence of specific symptoms). Many different diagnostic schemes have been in use. Recently, on the basis of the available data, the diagnostic criteria previously recommended by NDDG or WHO were modified. According to the revised criteria by the Expert Committee [1997], the ‘normal values’ and the ‘diagnostic values’ for diabetes (which do not coincide with the goals of therapy) are as follows (values given in the text refer to venous plasma glucose which is the preferred measurement; equivalents for whole blood and capillary glucose estimations, according to the IDF guidelines [1999] to type 2 diabetes, are indicated in footnotes).
Normal Values. The upper limit of normal venous plasma values has been set at 110 mg/dl (6.1 mmol/l) for FPG and at 140 mg/dl (7.8 mmol/l) for the 2-hour value after glucose load (OGTT).
Diagnostic Values. (a) FPGq126 mg/dl (or 7.0 mmol/l)1 after a fasting of at least 8 h, confirmed on a subsequent day, to rule out a labeling or technical error; (b) 2-hour value during OGTT q200 mg/dl (or 11.1 mmol/l)2, confirmed in a repeated test to make the final diagnosis; (c) symptoms of diabetes and a casual valueq200 mg/dl (or 11.1 mmol/l) at any time of day.
For epidemiological studies, diabetes prevalence and incidence should be estimated by a FPG q126 mg/dl. The value of FPG was changed from the previous value (q140 mg/dl) to current value (q126 mg/dl), because (1) the cutpoint of FPG q140 mg/dl defines a greater degree of hyperglycemia than did the cutpoint of the 2-hour value q200 mg/dl, and (2) this degree of hyperglycemia usually reflects a serious abnormality associated with serious chronic diabetic complications. The 2-hour value q200 mg/dl has been retained for the diagnosis of diabetes because it was well accepted, and enormous clinical and epidemiological data are based on this cutpoint value. The criteria for diagnosis of diabetes in an asymptomatic child should be stricter than those for the adults to avoid overdiagnosis of diabetes, and it should be considered that normal children commonly present OGTT values lower than adults. The diagnostic values for GDM as proposed by O’Sullivan and Mahan [1993], revised by NDDG and adopted by ADA and the American College of Obstetricians and Gynecologists (ACOG), are set lower than those for nonpregnant adults. A screening test is indicated between 24 and 28 weeks of gestation in asymptomatic female patients at risk, and a value 1 h after a 50 g of glucose load q140 mg/dl (or 7.8 mmol/l) can identify the individuals at risk for GDM in whom a full diagnostic 3-hour OGTT with 100 g of glucose should be performed. GDM occurs with an FPG q105 mg/dl (or 5.8 mmol/l) and a 2-hour value during OGTTq165 mg/dl (or 9.2 mmol/l). An intermediate metabolic state was introduced, which is characterized by glucose levels above those considered as normal but below those accepted for the diagnosis of diabetes mellitus. Referring to the fasting state, this condition was named impaired fasting glycemia or IFG (FPG q110 but p126 mg/dl or q6.0 but p7.0 mmol/l)3. Referring to the postload state, it was named impaired glucose tolerance or IGT (2-hour postload value in OGTT q140 mg/dl but p200 mg/dl or q7.8 but p11.1 mmol/l)4, without spontaneous hyperglycemia). IFG or IGT are not clinical entities but rather risk factors for future type 2 diabetes and cardiovascular disease, being associated with the metabolic syndrome or insulin resistance syndrome, characterized by abdominal or visceral obesity, hypertension, dyslipidemia (hypertriglyceridemia and low HDL value) and hyperuricemia. Conversion of IGT to type 2 diabetes takes years or decades and occurs in about 10–50% of IGT patients. Thus, IGT may not progress to overt diabetes and may revert to normoglycemia, especially in obese patients after dietary treatment and weight reduction.
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