Diabetes mellitus

Diabetes mellitus


137KB Sizes 0 Downloads 137 Views

0891–8422/02 $15.00  .00


DIABETES MELLITUS Dara P. Schuster, MD, and Vani Duvuuri, MD

DEFINITION OF DIABETES MELLITUS Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes mellitus is associated with long-term damage, dysfunction, and failure of various organs especially the eyes, kidneys, nerves, heart, and blood vessels.4 This article briefly reviews the definition, classification, diagnostic criteria, management, and acute and chronic complications of diabetes mellitus.

INCIDENCE AND PREVALENCE Based on the National Health Interview Survey (NHIS), in 1993 approximately 7.8 million people in United States had been diagnosed with diabetes mellitus, of whom 90% to 95% seemed to have type 2 (non-insulin dependent) diabetes mellitus. Prevalence rates of type 2 diabetes were 1.3% between the ages of 18 to 44 years, 6.2% at age 45 to 64 years, and 10.4% at ages above 65 years. The number of cases of type 1 (insulin-dependent) diabetes mellitus in the United States is approximately 300,000 to 5000,000. Approximately 625,000 new cases of diabetes mellitus are diagnosed annually in the United States.30

From the Division of Endocrinology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio





CLASSIFICATION AND DIAGNOSIS The National Diabetes Data Group (NDDG) in the United States developed the current diagnostic criteria and classification of diabetes mellitus, which were published in 1979. Based upon these data and on the rationale which was accepted in 1979, along with the research findings of the past 18 years, the Expert Committee of the American Diabetic Association has developed new criteria for the etiologic classification of diabetes mellitus4: Etiologic classification of diabetes mellitus 1. Type I diabetes (beta-cell destruction, usually leading to absolute deficiency) a. Immune-mediated Classic autoimmune diabetes presenting with ketosis Late autoimmune diabetes of adults (LADA) b. Idiopathic 2. Type 2 diabetes (insulin resistance and relative insulin deficiency) 3. Other specific types a. Genetic defects of beta-cell function Maturity onset of diabetes of youth (MODY) types 1 to 5 Mitochondrial DNA mutation b. Genetic defects in insulin action Type A insulin resistance Rabson-Mendenhall syndrome Lipoatrophic diabetes Others c. Disease of exocrine pancreas Pancreatitis Trauma or pancreatectomy Neoplasia Cystic fibrosis Hematochromatosis Fibrocalculous pancreatopathy Others d. Endocrinopathies Acromegaly Cushing’s syndrome Glucagonoma Hyperthyroidism Somatostatinoma Aldosteronoma Pheochromocytoma Others



e. Drug or chemically induced Vacor Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazoxide Beta adrenergic agonists Thiazides Dilantin Alfa-interferon Others f. Infections Congenital rubella Cytomegalo virus Others g. Uncommon forms of immune-mediated diabetes Stiff man syndrome Anti-insulin receptor antibodies Others h. Other genetic syndromes sometimes associated with diabetes Down syndrome Kliefelter’s syndrome Turner syndrome Wolfram’s syndrome Friedreich’s ataxia Huntington’s chorea Laurece-Moon-Biedl syndrome Mytonic dystrophy Porphyria Prader-Willi syndrome Others 4. Gestational diabetes mellitus

TYPE 1 DIABETES MELLITUS Type 1 diabetes mellitus results from cellular autoimmune beta-cell destruction of the pancreas, leading to absolute insulin deficiency.7 Type 1 diabetes mellitus previously has been known as insulin-dependent diabetes mellitus, juvenile-onset diabetes, ketosis-prone diabetes, and brittle diabetes of youth. Type 1 diabetes mellitus most commonly occurs in childhood, but it can occur at any age, even in the eighth and ninth decades of life. The onset of type 1 diabetes mellitus is quite variable,



usually rapid in infants and children and slow in adults. Some children and adolescents may present with ketoacidosis as the first manifestation of the disease, whereas others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and ketoacidosis in the presence of infection or stress. Others, particularly adults, may retain residual beta-cell function sufficient to prevent ketoacidosis for many years.56 Many individuals with this form of type 1 diabetes mellitus eventually become dependent on insulin for survival and are at risk of ketoacidosis. At this latter stage, there is little or no insulin, as noted by low or undetectable levels of C peptide. Although insulin secretion is severely decreased in type 1 diabetes mellitus, short periods of normal glucose homeostasis and insulin release may be seen in the type 1 diabetic patient shortly after diagnosis. This period is termed the honeymoon phase and can occur for as long as 6 to 12 months after diagnosis.

Pathogenesis of Type 1 Diabetes Mellitus Genetics of Type 1 Diabetes Mellitus The lifelong risk of type 1 diabetes mellitus for a close relatives of patients with type 1 diabetes mellitus averages 6% in offspring, 5% in siblings, and 30% in identical twins. The risk of type 1 diabetes mellitus for persons with no family history is 0.4%.7, 40, 36 A monozygotic twin of a patient with type 1 diabetes mellitus is at higher risk than a dizygotic twin, the risk for dizygotic twins of a patient with type 1 diabetes is similar to that in other siblings.36 The major susceptibility locus for type 1 diabetes mellitus is on the short arm of chromosome 6 in the HLA class II region. This locus provides 40% to 50% of the inheritable diabetic risk.15, 22 The histocompatibility antigens most commonly associated with type 1 diabetes mellitus are DR3, DR4, B8, and B15.22 The HLA alleles are thought to be associated through linkage disequilibrium to the immune response (or self-recognition) genes. In contrast, the DQA1*102,DQB1*602 heterodimer found on HLA-DR2 haplotypes confers dominant protection from the development of type 1 diabetes mellitus. Environmental Factors Viruses that have been implicated in the ultimate destruction of beta cells in type 1 diabetes mellitus include cocksackie B, mumps, and cytomegalovirus. Viruses can trigger beta-cell destruction by any of three mechanisms: (1) direct cellular destruction, (2) generation of cytokines that damage beta cells, or (3) molecular mimicry.42 Following beta-cell injury in type 1 diabetes mellitus, an immune response is associated with



the release of beta-cell antigens into the circulation with the subsequent formation of islet-cell antibodies. The markers of the immune destruction of the beta cell include islet-cell autoantibodies (ICA), autoantibodies to insulin (IAA), autoantibodies to glutamic decarboxylase (GAD65), and autoantibodies to tyrosinephosphatases (IA-2).6 Titers of these antibodies predict the risk of type 1 diabetes mellitus and are present within first year of onset. The antibodies generally decrease in time (20% after 5 years). The cell-mediated immune response (killer T lymphocytes or NK cells) may also be involved in the pathogenesis of type 1 diabetes mellitus. Other autoimmune disorders such as Grave’s disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, pernicious anemia, and celiac disease have been associated with type 1 diabetes mellitus.22

TYPE 2 DIABETES MELLITUS Type 2 diabetes mellitus (relative insulin deficiency or insulin resistance) is also referred to as noninsulin-dependent diabetes mellitus or adult-onset diabetes mellitus. Early insulin resistance and hyperinsulinemia characterize type 2 diabetes mellitus in the prediabetic phase, which is followed by subsequent failure of insulin secretion with resultant hyperglycemia and overt diabetes mellitus. Pathogenesis of Type 2 Diabetes Mellitus Understanding the pathogenesis of type 2 diabetes mellitus is complicated by several factors. Individuals may present with insulin resistance, insulin deficiency, or a combination of both. The clinical features can arise from genetic and environmental factors, making it difficult to determine the exact cause in an individual patient. Impaired Insulin Secretion and Insulin Resistance It is uncertain whether insulin resistance causes insulin deficiency or whether both are necessary to cause overt type 2 diabetes mellitus.33, 52 In most type 2 diabetic patients, insulin resistance precipitates a relative insulin deficiency, which then leads to hyperglycemia. In a normal individual who develops insulin resistance, insulin secretion is appropriately increased to overcome the insulin resistance, and normal glucose metabolism is maintained. In individuals with the genetic predisposition to develop type 2 diabetes mellitus, both insulin resistance and impaired insulin secretion contribute to the development of hyperglycemia. A small percentage of type 2 diabetics have no insulin resistance and have



a marked beta-cell deficiency. In contrast, some type 2 diabetics have severe insulin resistance and only a minor deficiency in insulin secretion. Impaired Insulin Processing In normal individuals, insulin is produced from cleavage of proinsulin. Ten percent to 15% of the insulin secreted is proinsulin. The processing of proinsulin to insulin in the beta cells is impaired in type 2 diabetics. The percentage of proinsulin is elevated to 40% in patients with the type 2 diabetes mellitus.41 Role of Islet Amyloid Polypeptide Islet amyloid polypeptide is stored in insulin-secreting granules in the pancreatic beta cells. It is cosecreted with insulin, resulting in serum concentration of insulin/islet amyloid peptide of about 1/10 and is increased in patients with type 2 diabetes mellitus. A high concentration of amylin decreases glucose uptake and inhibits endogenous insulin secretion; this finding suggests that amylin may be involved directly in the pathogenesis of type 2 diabetes mellitus.28 The causative role of amylin in type 2 diabetes mellitus is unclear, and there is no apparent association between the amylin gene and type 2 diabetes mellitus. Impaired Hepatic Glucose Production The maintenance of normal glucose tolerance after glucose ingestion depends on the following mechanisms16: • stimulation of insulin by hyperglycemia • suppression of hepatic glucose production by the resultant hyperinsulinemia and hyperglycemia • stimulation of glucose uptake by peripheral tissues, primarily by muscle, in response to hyperinsulinemia and hyperglycemia In type 2 diabetics with established fasting hyperglycemia above 140 mg/dL, there is excessive hepatic glucose production even though insulin levels are increased by two- to four-fold. Recent studies have shown that accelerated gluconeogenesis is the major abnormality responsible for the increased rate of basal hepatic glucose production.16 Genetics of Type 2 Diabetes Mellitus The genetic predisposition for type 2 diabetes is stronger than that for type 1 diabetes mellitus.36 The genetics of type 2 diabetes mellitus are complex, however, and are not clearly defined. The risk of type 2



diabetes mellitus in a monozygotic twin of an affected person is 60% to 90%.8 The lifetime risk of type 2 diabetes mellitus for a first-degree relative of a person with type 2 diabetes mellitus is 5 to 10 times higher than for age- and weight-matched persons without a family history. Thirty-nine percent of patients with type 2 diabetes mellitus have at least one parent with the disease. Genetic Defects of Beta Cells Maturity-onset diabetes mellitus of the young is characterized by impaired insulin secretion and is associated with monogenetic defects in beta-cell function. Three abnormal genetic loci have been identified on different chromosomes. The most common is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)–1␣.47 A second form, MODY 2, is associated with mutations in the glucokinase gene on chromosome 7p. The defect in the glucokinase gene requires increased plasma levels of glucose to elicit normal levels of insulin secretion and results in a defective glucokinase molecule.10 Genetic Defects in Insulin Action The first step in insulin action involves binding of the hormone to a specific insulin receptor that is present in many cells throughout the body. In persons with type 2 diabetes, both the number of insulin receptors on the cell surface and the binding affinity of insulin to its receptor are diminished.40 There are five glucose transport units.17 The insulin-stimulated glucose transporter (GLUT4) is in the muscle. The GLUT4 transporter is inserted into the cell membrane and activated in response to insulin. Glucose enters the cell and then is either phosphorylated into glucose6-phosphate by hexokinase and subsequently converted into glycogen or is oxidized. Multiple intracellular defects have been identified in type 2 diabetes mellitus. The first intracellular defect is an inability of insulin to activate the insulin receptor by stimulating tyrosine phosphorylation by the insulin receptor. The ability of insulin to phosphorylate IRS-1 (insulin recepter substrate-1) and PI-3 (insulin recepter substrate-1) kinase are impaired. The defects in muscle glucose phosphorylation by hexokinase 11, glycogen synthase, and pyurvate dehydrogenase have been well described in type 2 diabetes mellitus. Which of these intracellular defects are primary and which are secondary to diabetes mellitus remains to be elucidated.



Environmental Factors Role of Obesity. The mechanism by which obesity induces insulin resistance is poorly understood, but a high concentration of plasma free fatty acid and the pattern of fat distribution are important factors. Plasma free fatty acids are high in obese patients. Increased plasma concentrations of free fatty acid cause insulin resistance by decreasing insulin-mediated glucose transport into the cell.12, 38 Most studies suggest that visceral adiposity rather than subcutaneous or total adiposity is the significant determinant of insulin resistance. Mutation of the gene for ␤3 adrenergic receptor is associated with obesity and type 2 diabetes mellitus.53 GESTATIONAL DIABETES MELLITUS Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity with onset or first recognition during the current pregnancy. The overall prevalence of gestational diabetes mellitus in the United States is 2% to 5%.4 Screening for Gestational Diabetes Mellitus It was previously recommended that screening for gestational diabetes mellitus be performed in all pregnancies. This approach is not costeffective. Certain factors place women at low risk for the development of glucose intolerance during pregnancy31: • • • •

age less than 25 years normal body weight no first-degree relatives with diabetes no abnormal history of glucose metabolism or poor obstretic outcome • not a member of an ethnic or racial group with a high prevalence of diabetes (Hispanic American, Native American, African-American, Pacific Islander) Table 1 summarizes the criteria for the diagnosis of gestational diabetes mellitus.4 NEW CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUS The diagnostic criteria for diabetes mellitus are based upon the new American Diabetes Association recommendations published in 1997.




95 180 155 140

mg/dL mg/dL mg/dL mg/dL*

75-gram Glucose Load 95 mg/dL 180 mg/dL 155 mg/dL —

*There are two criteria based on results of the 3 hour glucose tolerance test. According to the participants of the Fourth International Workshop Conference on GDM, GDM is present if two or more of the plasma glucose values are exceeded. These values are lower than those proposed by the NDDG group, which used cutoff values of 105, 190, 160, and 145 mg/dL. GDM  gestational diabetes mellitus; NDDG  National Diabetes Data Group

There are three ways to diagnose diabetes mellitus, and unless the patient experiences unequivocal hyperglycemia with acute metabolic decompensation, each must be confirmed on a subsequent day: 1. Symptoms of diabetes plus casual plasma glucose concentration above 200 mg/dL (11.1 mmol/L). (Casual is defined as occurring at any time of day, without regard to time elapsed since the last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.) or 2. Fasting plasma glucose (FPG) above 126 mg/dL (Fasting is defined as no calorie intake for at least 8 hours.) or 3. 2-hour plasma glucose above 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT). The test should be performed in accordance with World Health Organization (WHO) criteria using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water. This measure is not recommended for routine clinical use. These criteria for the diagnosis of diabetes mellitus with fasting plasma sugars above 126 mg/dL are based on epidemiologic studies. The long-term prospective studies demonstrate that 10% to 15% of individuals with fasting plasma glucose levels above 126 mg/dL develop diabetic retinopathy within 10 years. Other Definitions The Expert Committee of the American Diabetes Association (ADA) recognizes an intermediate group of persons who do not meet the criteria for diabetes mellitus but whose glucose levels are too high to be



Table 2. DIAGNOSTIC CRITERIA FOR INTERMEDIATE GROUPS–ADA RECOMMENDATIONS, 1997 FPG (mg/dL) Normal glucose tolerance Impaired fasting plasma glucose Impaired glucose tolerance Diabetes mellitus

2-Hour Plasma Glucose (mg/dL)

⬍ 110 110–125 ⬎ 126

⬍ 140 — 140–199 ⬎ 200

ADA  American Diabetes Association; FPG  fasting plasma glucose

considered normal. Table 2 summarizes the diagnostic criteria for the intermediate groups.4

SCREENING CRITERIA FOR TESTING FOR DIABETES MELLITUS IN ASYMPTOMATIC, UNDIAGNOSED INDIVIDUALS: RECOMMENDATIONS OF THE AMERICAN DIABETES ASSOCIATION Testing for diabetes mellitus should be considered in all individuals at age 45 years and above. If results are normal, testing should be repeated at 3-year intervals.4 Testing should be considered at a younger age or be carried out more frequently in individuals who • are obese (who weigh more than 120% of their desirable body weight or have a body mass index (BMI) above 27 kg/m2) • have a first-degree relative with diabetes mellitus • are members of a high-risk ethnic population (e.g., African-American, Hispanic American, Native american, Asian American, Pacific Islander) • have delivered a baby weighing more than 9 pounds or have been diagnosed with gestational diabetes mellitus • are hypertensive (blood pressure above 140/90 mm Hg) • have a high-density lipoprotein (HDL) cholesterol level above 35 mg/dL and triglyceride levels above 250 mg/dL • on previous testing had IGT OR IFG Fasting plasma glucose or an oral glucose tolerance test (OGTT) may be used for diagnosis of diabetes mellitus, but fasting plasma glucose levels are greatly preferred in the clinical setting because of their convenience, lower cost, acceptability, and ease of administration.



MANAGEMENT OF DIABETES MELLITUS Diabetes mellitus is a chronic illness that requires continuing medical care and education to prevent acute complications and to reduce the risk of long-term complications. Diabetes mellitus care should be provided by a physician-coordinated team that includes physicians, nurses, dietitians, and mental health professionals with expertise and a special interest in diabetes mellitus. As summarized in Table 3, lowering blood glucose to normal or nearly normal levels has proven benefits for patients with diabetes mellitus.5 • The decompensation caused by diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome and associated morbidity and mortality are reduced markedly. • The symptoms of blurred vision and the risk of polyuria, polydipsia, fatigue, weight loss with polyphagia, and vaginitis may be decreased. • The risks of development or progression of diabetic retinopathy, nephropathy, and neuropathy all are greatly decreased. • Near-normalization of blood glucose level has been associated with a less-atherogenic lipid profile.

Specific Goals of Treatment Type 1 Diabetes Mellitus The glycemic target goals are based on prospective, randomized clinical trials, most notably the Diabetes Control and Complications Trial (DCCT).43 This trial demonstrated, in patients with type 1 diabetes mellitus, a 50% to 70% reduction in the risk of development or progression of retinopathy, nephropathy, and neuropathy by intensive treatment regimens when compared with conventional treatment regimens.17


HbA1c reduction Retinopathy Nephropathy Neuropathy Macrovascular disease



9%–7% 63% 63% 54% —

8%–7% 17–21% 24–33% — 16%

HbA1c  hemoglobin A1c ; DCCT  Diabetes Control and Complications Trial; UKPDS  United Kingdom Prospective Diabetes Study



Achieving nearly normal glucose levels with intensive insulin treatment to prevent complications requires15 • frequent self-monitoring of blood glucose (SMBG) (at least 3 to 4 times/day) • medical nutrition therapy • patient education in self-management and problem solving Other factors that may increase the risk or decrease the benefit of intensive treatment are advanced cardiovascular disease or cerebrovascular disease, advanced age, and coexisting disease that shortens life expectancy. Type 2 Diabetes Mellitus The goals of glycemic control in type 2 diabetes mellitus are the same as those for type 1 diabetes mellitus, whether treated with insulin, hypoglycemic agents, or both, as outlined in Table 4. In type 2 diabetes mellitus, the United Kingdom Prospective Study (UKPDS) has shown a relationship between hyperglycemia and microvascular disease similar to that shown in the DCCT trials in type 1 diabetes mellitus. Analysis of the UKPDS data has shown45–48 that • Improved blood glucose control is associated with reduced risk of developing retinopathy, nephropathy, and possibly reduced neuropathy. • The overall microvascular complication rate was decreased by 25% in patients receiving intensive therapy versus conventional therapy. • There is a continuous relationship between the risk of microvascular complications and glycemia: for every percentage-point decrease in hemoglobin A1C (HbA1C) there is a 35% reduction in microvascular complications.

Table 4. GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES Glucose Values (mg/dL) Whole Blood Preprandial glucose Bedtime glucose Plasma Values Preprandial glucose Bedtime glucose HbA1c (%) HbA1c  hemoglobin A1c



Action Suggested

⬍100 ⬍110

80–120 100–140

⬍80/⬎140 ⬍100/160

⬍110 ⬍120 ⬍6

90–130 110–150 ⬍7

⬍90/⬎150 ⬍110/⬎180 ⬎8



• Aggressive control of blood pressure, consistent with ADA recommendations, significantly reduces strokes, diabetes-related deaths, heart failure, microvascular complications, and visual loss. Treatment of type 2 diabetes mellitus should emphasize management of multiple risk factors. Such treatment should include medical nutrition therapy, exercise, weight reduction when indicated, and use of oral glucose-lowering agents or insulin. Attention should be given to cardiovascular risk factors, including hypertension, smoking, dyslipidemia, and family history.5

History and Physical Examination The history should include symptoms of hyperglycemia, nutrition history, exercise history, frequency and severity of acute complications (e.g., diabetic ketoacidosis (DKA), nonketotic hyphosmolar coma [NKHS]), symptoms of chronic complications, family history of diabetes mellitus, risk factors for atherosclerosis, smoking, hypertension, hyperlipidemia, and so forth.5 The physical examination should focus on detection of complications of diabetes mellitus that affect eye, nerve, kidney, foot, skin, cardiac, and vascular systems.

Laboratory Evaluation The following tests should be performed to determine the degree of glycemic control and to define associated complications and risk factors: FPG, HbA1C, fasting lipids profile, total cholesterol, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. The urinalysis should be examined for glucose, protein, ketones, and sediment, and urine culture should be performed if sediment is abnormal or symptoms are present. The serum creatinine level should be followed in adults and in children if proteinuria is present. A test should be performed for microalbuminuria (timed-specimen or the albumin/creatinine ratio) in pubertal and postpubertal patients with type 1 diabetes mellitus who have had diabetes for at least 5 years and in all patients with type 2 diabetes mellitus. Thyroid-stimulating hormone should be checked in all type 1 patients on a yearly basis, and adults should have a baseline electrocardiogram.5



Health Maintenance Health-maintenance measures recommended by the ADA5 for diabetic patients are for comprehensive annual dilated eye and visual examinations by an ophthalmologist or optometrist for all patients aged 10 years and older who have had diabetes mellitus for 3 to 5 years, for all patients diagnosed after age 30 years, and for any patient with visual symptoms or abnormalities • dental hygiene • influenza vaccination annually; pneumococcal vaccination • foot examination in patients at risk at least once a year to identify high-risk conditions. This examination should include an assessment of protective sensation, foot structure, biomechanics, vascular status, and skin integrity. Persons with neuropathy should have visual inspection of their feet at every contact with a health care professional. • quarterly HbA1C evaluation if treatment changes or the patient is not meeting goals; twice-yearly evaluation if stable • fasting lipid profile annually • urinalysis for protein annually • microalbumin measurement annually (if urinalysis is negative for protein) Treatment regimens of diabetes mellitus include diet, exercise, and oral glucose-lowering agents or insulin Diet A proper diet is a fundamental element of therapy in all patients with diabetes mellitus. Adherence to nutrition therapy is one of the most challenging aspects of diabetes care. The reasons include complexity of dietary instructions and poor understanding of the dietary control by the physician and the patient. Because of the complexity of nutritional issues, it is recommended that a registered dietitian who is knowledgeable and skilled in implementing the diabetic’s medical nutrition therapy be the team member providing nutrition care and education. Today there is no single diabetic or ADA diet. The recommended diet can only be defined as a nutrition prescription based on assessment and treatment goals and outcomes.2 Nutrition Therapy and Type 1 Diabetes Mellitus A meal plan based on an individual’s food intake should be determined and used as the basis for integrating insulin therapy into the



usual eating and exercise patterns. Individuals using insulin therapy should eat at consistent times synchronized with the action-time of the insulin preparation used. Intensified therapy involving multiple daily injections or continuous subcutaneous insulin infusion (CSII) allows more flexibility in the timing of meals and snacks and in the amount of food eaten. Nutrition Therapy and Type 2 Diabetes Mellitus The primary medical nutrition therapy goals for individuals with type 2 diabetes mellitus are to achieve and maintain glucose, lipid, and blood pressure target goals. Hypocaloric diets and weight loss usually improve short-term glycemic levels and have the potential to improve long-term metabolic control. Traditional dietary strategies and even lowcalorie diets cannot achieve long-term weight loss, however. The reason is unclear. A moderate caloric restriction (200–500 calories less than the average daily intake) and nutritionally adequate meal plans with a reduction of total fat (especially saturated fat), accompanied by an increase in physical activity, should be recommended. A hypocaloric diet, independent of weight loss, is associated with increased sensitivity to insulin and improvement of blood glucose levels. A moderate weight loss of 5 to 9 kg, irrespective of starting weight, has been shown to reduce hyperglycemia, dyslipidemia, and hypertension. Spacing of meals (spreading nutrient and particularly carbohydrate intake) throughout the day is another strategy that can be adopted. Oral glucose-lowering agents or insulin may be added to medical nutrition therapy if metabolic control has not improved. Protein Protein requirements for people with diabetes mellitus are the same as for the general population, that is, 10% to 20% of daily caloric intake. With the onset of overt nephropathy, a lower intake of protein (0.8 g/ kg/day) should be considered. It has been suggested that once the glomerular filtration rate begins to fall, further restriction to 0.6 kg/day may prove useful in slowing the decline.26 Total Fat For people with diabetes mellitus, 25% to 30% of total calories should be contributed by fat. The distribution of calories from fat and carbohydrate can vary and can be individualized based on the nutrition



assessment and treatment goals. Cholesterol intake should be less than 300 mg, and less than 10% of total calories should be from saturated fat. Fiber Daily consumption of a diet containing 20 to 35 g of soluble and insoluble dietary fiber from a wide variety of food sources is recommended. Alcohol The ADA dietary guidelines recommend no more than two drinks/ day for men and no more than one drink/day for women.2 The effect of alcohol on blood glucose levels depends on the amount of alcohol ingested and on the relationship to food intake. Alcohol is not metabolized to glucose and inhibits gluconeogenesis; therefore, if persons treated with insulin or oral glucose-lowering agents consume alcohol without food, hypoglycemia can result. Hypoglycemia can occur at blood alcohol levels that do not exceed mild intoxication. Exercise Exercise improves insulin sensitivity, lowers blood glucose levels, reduces cardiovascular morbidity, and may prevent the development of type 2 diabetes mellitus in high-risk groups.50, 51, 57 For type 1 diabetes, exercise, although necessary and beneficial, can be somewhat problematic. The counter-regulatory hormonal adaptations are lost in patients with type 1 diabetes mellitus. As a consequence, when such individuals have too little insulin in circulation because of inadequate therapy, an excessive release of counterregulatory hormones may aggravate already high levels of glucose and ketones and can even precipitate ketoacidosis. The presence of high levels of insulin caused by exogenous insulin administration can attenuate or prevent the mobilization of glucose and other substrates induced by exercise. As a result, hypoglycemia may ensue. In patients with type 2 diabetes mellitus treated with an oral hypoglycemic drug, exercise tends to lower blood glucose concentration. This effect may depend on the timing of the patient’s meal. Hypoglycemia tends to be less of a problem in patients with type 2 diabetes mellitus.1 Recommendations Regular exercise is likely to be beneficial in most diabetics, even in those with advanced, long-standing disease. The patient needs to be



enthusiastic and realistic. For those over 35 years of age, with diabetes duration of more than 10 years, any risk factor for coronary artery disease, the presence of microvascular disease, or peripheral vascular disease requires a complete physical examination and exercise stress test before beginning an exercise program.1

Prevention of Type 2 Diabetes Mellitus Preliminary studies have shown that physical activity of moderate intensity reduces the incidence of new cases of type 2 diabetes mellitus and the progression to overt type 2 diabetes mellitus. This finding led to the hypothesis that exercise may be useful in preventing or delaying the onset of type 2 diabetes mellitus. The National Institutes of Health is currently sponsoring a large, prospective, multicenter trial in the United States to clarify the feasibility of this approach.37, 44, 50

Oral Glucose-Lowering Agents Pharmacologic treatment with oral agents is indicated in patients with type 2 diabetes mellitus when diet and exercise fail to achieve acceptable glycemic control (HbA1C ⬎ 7%). Five classes of oral diabetic agents currently are approved for the treatment of type 2 diabetes mellitus in the United States. The goal of therapy is to reduce the HbA1C to less than 7%. Combination therapy in type 2 diabetes mellitus is indicated when plasma glucose levels are in excess of 180 to 200mg/dL and response with monotherapy is inadequate after 4 to 8 weeks.39 Table 5 illustrates the mechanism of action, dosing schedule, and side effects of the antidiabetic drugs.

Indications for Insulin Therapy Insulin is indicated for • patients with type 1 diabetes mellitus • patients with long-standing type 2 diabetes mellitus when combinations of two different classes of oral agents fail to achieve glycemic goals • pregnant patients • treating acute complications of diabetes mellitus, DKA, and NKHS

96 Table 5. ORAL GLUCOSE-LOWERING AGENTS Effects on Glycemia Mechanism

Dose Range (mg/day)

Insulin Secretagogues (Close KATP Channel in Beta Cell) Sulfonylureas Glipizide (Glucotrol, Stimulates pancreatic insulin 5 to 20 before meals once Glucotrol XL ) secretion or twice a day Glyburide (DiaBeta, Stimulates pancreatic insulin 1.25 to 20 (0.75 to 12 for Micronase, Glynase) secretion Glynase only) with meals once daily b.i.d. or t.i.d. Glimepiride (Amaryl) Stimulates pancreatic insulin 1 to 4 (maximum 8) once secretion, increases tissue daily with meal sensitivity to insulin Meglitinides Repaglinide (Prandin) Increases pancreatic insulin 1.5 to 12 (maximum 16) secretion and requires taken only with meals presence of glucose for its (no more than 30 min action before first bite), t.i.d. or q.i.d. Nateglinide (Starlix) Increases pancreatic insulin secretion and requires presence of glucose for its action

Units FPG앗 HbA1c앗%



Side Effects

Hypoglycemia Hypoglycemia





a-Glucosidase Inhibitors (Delay Digestion and Absorption of Complex Carbohydrates) Acarbose (Precose) Delays glucose absorption 75 to 150 (maximum 300) 20–30 by inhibiting pancreatic awith first bite of each glucosidase enzymes meal, t.i.d. Miglitol (Glyset) Delays glucose absorption 150 to 300 (Bayer Corporation, by inhibiting pancreatic aWest Haven, CT) glucosidase enzymes Biguanides (Insulin Sensitizers) Metformin Decreases hepatic glucose 1000 to 2500 with meals, (Glucophage) production, increases b.i.d. or t.i.d. (Bristol–Mayers Squibb, peripheral glucose uptake Princeton, NJ) and use Thiazolidinediones (Insulin Sensitizers) Rosiglitazone (Avandia) Improves insulin sensitivity (Smith, Kline, Beecham, in muscle and adipose Pittsburgh, PA) tissue, decreases hepatic Pioglitazone (Actos) gluconeogenesis (Jakeda Pharmaceuitials, Linconshire, IL)

4 to 8 once daily, or may be divided b.i.d. 15 to 45


Elevated serum transaminases (AST or ALT), flatuence, diarrhea, abdominal pain, may increase the hypoglycemic potential of sulfonylureas



Lactic acidosis, diarrhea, nausea, vomiting, abdominal bloating, anorexia WARNING: Contraindicated in patients with renal insufficiency (creatinine ⱖ 1.5 if male, ⱖ 1.4 if female)



Edema, decreased hematocrit Rosaglitazone and pioglitazone are contraindicated in patients with active liver disease or ALT ⬎2.5 times the upper limit of normal. Because of the association of hepatocellular injury with the thiazolidinedione class (troglitazone), current manufacturer recommendation is transaminase assessment every other month for the first 12 months of therapy, and periodically thereafter.

FPG  fasting plasma glucose; HbA1c  hemoglobin A1c ; KATP  potassium channels; AST  aspartate aminotransferase; ALT  alanine aminotransferase; b.i.d.  two times/day; t.i.d.  three times/day




Table 6 summarizes the different types of insulin, onset and peak of action, and adverse effects.33

COMPLICATIONS OF DIABETES MELLITUS Acute Complications Diabetic ketoacidosis and NKHS are the two most serious acute metabolic complications of diabetes mellitus. These disorders can occur in both type 1 and type 2 diabetes mellitus. The mortality rate in patients with diabetic ketoacidosis is less than 5% in experienced centers, whereas the mortality rate in patients with hyperosmolar hyperglycemic state still remains high, at approximately 15%.

Diabetic Ketoacidosis and Nonketotic Hyperosmolar State Diabetic ketoacidosis occurs as a result of severe insulin deficiency and an excess of counterregulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone. The combination of insulin deficiency and increased counterregulatory hormones in DKA leads to the release of free fatty acids into the circulation from adipose tissue and hepatic fatty acid oxidation to ketone bodies (beta-hydroxybutyrate and acetoacetate), with resulting ketonemia and metabolic acidosis. The NKHS syndrome occurs predominantly in patients with type 2 diabetes mellitus and is caused by a plasma insulin concentration that is inadequate to facilitate glucose use by insulin-sensitive tissues but is adequate to prevent lipolysis and subsequent ketogenesis. Diabetic ketoacidosis and NKHS are associated with glycosuria, leading to osmotic diuresis with loss of water, sodium, potassium, and other electrolytes.32 Precipitating Factors The most common precipitating factor in the development of DKA is infection. Other precipitating factors include cerebrovascular accident, alcohol abuse, pancreatitis, myocardial infarction, trauma, and drugs (␤blockers, thiazide, glucocorticoids, phenytoin, didanosine, and somatostatin). In addition, new-onset type 1 diabetes mellitus or discontinuation of or inadequate insulin in established type 1 diabetes mellitus commonly leads to the development of DKA. Elderly individuals with newonset diabetes or individuals with known diabetes mellitus who are


Onset of Action

Peak Action (hrs)

Duration of Action (hrs)

Adverse Effects


Rapid-acting Insulin lispro (Humalog) Lilly

5–15 min



Hypoglycemia, lipodystrophy

Insulin lispro injection, whether alone or mixed with a longer-acting insulin, must be timed immediately within 15 min before the beginning of a meal.

Short-acting Regular human insulin (Humulin R, Lilly) (Novdin R, Nova Noodisk)

30–60 min



Hypoglycemia, lipodystrophy

Regular human insulin is also appropriate for intravenous use in the hospital setting. With intravenous use, the onset and peak effect (30–90 min) will be earlier than with subcutaneous injection.

1–3 hrs



Hypoglycemia, lipodystrophy

1–3 hrs



Hypoglycemia, lipodystrophy

Lente insulin should not be mixed with NPH insulin. Mixing of regular and Lente insulins is not recommended except for patients already well controlled on this combination, because this admixture may delay the onset of the short-acting insulin

2–4 hrs



Same as above

Typical duration of effect: up to 28 hours after injection

1–3 hrs



Intermediate-acting NPH, human insulin isophane suspension (Humulin N, Lilly) Indianopdis, IN Lente human insulin Insulin zinc suspension (Humulin L, Lilly) (Novolin L Nova Noodisk, Princeton,NJ) Long-acting Ultralente (extended insulin zinc suspension) (Humulin U, Lilly) (Lantus Coecombinart DNA oogin, Aventis Pharmaceuticals, Bridgeport, NJ) Insulin glargine


Premixed Insulin 70/30 (70% Human insulin isophane suspension (NPH); 30% Buffered regular human insulin coecombinant DNA oogin) (Humulin 70/30-LillyIndianapolis, IN. Novolin 70/30-Novo Nordisk, Princeton NJ), 50/50 (50% Human insulin isophane suspension (NPH); 50% Regular human insulin injection (Recombinant DNA orgin) 75/25 (75% Insulin lispro protamine suspension; 25% Insulin lispro injection (Recombinant DNA orgin) (Humalog 75/25 mix) Lilly, Indianopolis, IN)

Availability anticipated Same as above

Mixtures of NPH and Regular/Lispro Human Insulin are available commercially and may be used if appropriate for a given patient’s insulin requirements. Commonly used preparations involve 70% or 75% NPH and 30% Regular or 25% Lispro or 50% of NPH and 50% Regular



unaware of hyperglycemia or are unable to take fluids when necessary are at risk for NKHS.

History and Physical Examination The initial evaluation should include a brief history and physical examination. The classic clinical picture includes a history of polyuria, polydipsia, polyphagia, weight loss, vomiting, abdominal pain, dehydration, weakness, clouding of sensorium, and finally coma. Physical findings include poor skin turgor, Kussmaul’s respiration, tachycardia, hypotension, altered mental status, shock, and coma. Hypothermia, if present, is a poor prognostic sign.

Laboratory Findings Laboratory evaluation in DKA reveals metabolic acidosis with an elevated anion gap and the presence of serum ketones. Plasma glucose concentration is always elevated. Other laboratory findings may include hyponatremia, hyperkalemia, increased serum urea nitrogen (BUN) and creatinine levels, hyperosmolality, and an elevation of serum amylase unrelated to pancreatic disease. Laboratory evaluations in NKHS are similar to those for DKA and should reveal hyperglycemia (often greater than 600 mg/dL), absence of ketonemia or mild ketonemia, and plasma osmolarity greater than 320 mOsm/L, arterial pH above 7.3, and bicarbonate above 15 mEq/L. Associated findings include severe azotemia and lactic acidosis.

Treatment Successful treatment of DKA and NKHS requires correction of dehydration with fluids, correction of hyperglycemia with insulin, correction of electrolyte imbalances, identification of comorbid precipitating events, and frequent monitoring.

Complications The most common complications of DKA include hyperglycemia caused by overzealous treatment with insulin, hypokalemia caused by insulin administration and treatment of acidosis with bicarbonate, and hyperglycemia resulting from the interruption or discontinuation of



intravenous insulin therapy after recovery without coverage with subcutaneous insulin. Cerebral edema may occur during therapy for DKA, manifested by headache, altered mental status, and papilledema. A computed tomographic (CT) scan of the head can establish the diagnosis.19 Hypoxemia and noncardiogenic pulmonary edema may complicate the treatment of DKA and NKHS. Chronic Complications Hyperglycemia is key in the development of microvascular complications in both type 1 and type 2 diabetes mellitus. Diabetes mellitus also is associated with premature macrovascular disease. The prevention or delay of the development or progression of the chronic complications of diabetes mellitus depends on the degree to which the metabolic abnormalities are chronically controlled. See Table 3, which summarizes the decreased incidence of chronic complications with good glycemic control. Macrovascular Complications Coronary artery disease, stroke, and myocardial infarction occur with increased frequency in diabetes mellitus. Heart disease should be suspected when dyspnea or unexplained hyperglycemia occur, even when angina is atypical or absent. Diabetes mellitus also is associated with cardiomyopathy characterized by heart failure in the absence of identifiable organic heart disease and normal coronary arteries. Atherosclerosis is extensive in diabetes mellitus and occurs earlier than in the general population. The cause of the accelerated course is not known. Atherosclerosis occurs in many sites. Peripheral deposits may cause intermittent claudication, and gangrene and impotence in men occur as a result of vascular disease or diabetic neuropathy.34 Diabetes mellitus is associated with increased platelet adhesiveness, add elevated levels of factor VIII, von Willebrand’s factors, and tissuetype plasminogen activator (PA) inhibitor type 1. Microvascular Complications Retinopathy. Diabetic retinopathy is the major cause of blindness among adults between the ages of 20 and 74 years in the United States. Blindness in diabetes occurs as a result of proliferative retinopathy and also because of an increased rate of cataracts and glaucoma.34 Diabetic retinopathy includes nonproliferative retinopathy (simple or background), which is limited to the retina (microaneurysms, retinal



infarcts) and proliferative retinopathy (neovascularization), extended anteriorly to the retina, obscuring underlying retinal details. Macular edema should be suspected when glasses do not correct the loss of visual acuity. Ophthalmologic consultation should be sought early, because the vision may be spared with laser therapy of macular edema. The two serious complications of retinopathy are vitreous hemorrhage and retinal detachment, manifest by sudden loss of vision.21 Treatment of diabetic retinopathy is photocoagulation. Prevention of diabetic retinopathy can be achieved by maintaining target glycemic and blood pressure goals. An annual examination by an ophthalmologist is recommended beginning at 5 years following the onset of type 1 diabetes mellitus (or at puberty) and at the time of diagnosis in type 2 diabetes mellitus or the onset of diabetes mellitus in patients 30 years or older. For pregnant patients with preexisting diabetes, eye examination is recommended before conception and during the first trimester.5 Diabetic Nephropathy. Diabetes mellitus is the leading cause of end-stage renal disease (ESRD) in the United States. About 20% to 30% of patients with type 1 or type 2 diabetes mellitus develop evidence of nephropathy, but a smaller percentage of patients with type 2 diabetes progress to end-stage renal disease. The four approaches to the prevention of diabetic renal disease are (1) control of glycemia, (2) treatment of hypertension, (3) restriction of protein, and (4) avoidance of nephrotoxic drugs. Glycemic control resulting from pancreas transplantation does not ameliorate advanced nephropathy, but it delays the progression of nephropathy in donor kidneys. Angiotensin-converting enzyme (ACE) inhibitors delay the onset and progression of diabetic nephropathy and also have a specific renoprotective effect. The use of ACE inhibitors prevents the progression of renal disease in patients with diabetes mellitus, even in the absence of hypertension. The calcium-channel blocks, diltiazem and nicardipine, decrease albuminuria and should be considered as alternative therapy when ACE inhibitors are contraindicated (in patients with renal artery stenosis or hyperkalemia).20 The ADA recommends testing for microalbuminuria (timed-specimen or albumin/ creatinine ratio) in pubertal and postpubertal patients with type 1 diabetes mellitus who have had diabetes mellitus for at least 5 years and in all patients with type 2 diabetes mellitus. Because of the variability in urinary albumin excretion, 2 or 3 specimens collected within a 3 to 6 month period should be abnormal before a patient should be considered as having crossed one of these diagnostic thresholds. Exercise within 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, and marked hypertension may elevate urinary albumin excretion over baseline values.5 Diabetic Neuropathy. Diabetic neuropathies are one of the most common and least recognized complications of diabetes mellitus. In a



DCCT trial, intensive treatment decreased the neuropathy by 60%. The diabetic neuropathies occur as sensorimotor peripheral neuropathies and autonomic neuropathies. Mononeuropathies commonly involve the third and sixth cranial nerves. The onset is sudden, and resolution is spontaneous. Diabetic amyotrophy, which manifests as wasting disease, resolves in 6 to 12 months of intensified glycemic control and physical therapy. The most common picture is peripheral neuropathy (sensorimotor neuropathy) which presents as severe dysesthesias, anorexia, and weight loss. There is no effective specific treatment. Treatment is symptomatic with antidepressants, and analgesics are occasionally effective. Resolution of symptoms is slow. Autonomic neuropathy may cause postural hypotension, persistent tachycardia, neurogenic bladder, gastroparesis, diarrhea, and impotence. Impaired visceral pain sensation can obscure symptoms of angina and myocardial infarction.14 Diabetic Foot Problems. Diabetic foot problems are the major cause of lower-limb amputations in diabetic individuals. Diabetic foot is a major manifestation of chronic neuropathy aggravated by vascular insufficiency and infection. The foot ulcers and infection result from a combination of anatomic deformities, sensory neuropathy that reduces pain and pressure perception, and vascular insufficiency. Specialized treatment is necessary to prevent and manage foot disease. Preventive foot care includes risk identification, foot examination, and prevention of highrisk conditions. The risk of ulcers or amputations is increased in people who have had diabetes mellitus 10 years, are male, have poor glucose control, or have cardiovascular, retinal, or renal complications. The footrelated conditions associated with increased risk of amputation are peripheral neuropathy with loss of protective function, altered biomechanics (bony deformity, callus), peripheral vascular disease, history of ulcer or amputation, and severe nail pathology.3 The foot examination includes assessment of protective function, foot structure, biomechanics, vascular status, and skin integrity. All individuals should receive an annual foot examination. Persons with neuropathy should have a visual inspection of their feet at every visit to a health care professional. Controlling glucose to nearly normal levels is the most effective means of preventing neuropathy. Smoking cessation should be recommended to reduce the risk of vascular disease. Management of High-Risk Conditions People with neuropathy or evidence of increased plantar pressure may be managed with well-fitted walking shoes or athletic shoes. Patients should be educated on ways to substitute other sensory modalities (hand palpation, visual inspection) for surveillance of early problems.



Symptoms of claudication require further vascular assessment. Ulcers should be evaluated for underlying pathology. Minor conditions such as dry skin and tinea pedis should be treated to prevent the development of a serious condition. Skin Lesions in Diabetes Mellitus Diabetic dermopathy (shin spots) are small, round plaques with raised borders, located at the anterior tibial surface. They crust at the edge and ulcerate centrally. Necrobiosis lipoid diabeticorum is a plaquelike lesion with a central yellowish area surrounded by a brown border. It is usually found over the anterior aspects of the legs. Infestation of skin with Candida and dermatophytes are common.

SUMMARY Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes mellitus is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. The management of this disease process is complicated. Good diabetic control depends on diligence in blood glucose monitoring, frequent adjustment of medications, adherence to a regular diet and exercise plan, and treatment of comorbid conditions such as hypertension and hyperlipidemia.

References 1. American Diabetes Association: Clinical practice recommendations 2001, diabetes mellitus and exercise [position statement] Diabetes Care 24 (suppl 1):S51–55, 2001 2. American Diabetes Association: Clinical practice recommendations 2001, nutrition recommendations and principles for people with diabetes mellitus [position statement]. Diabetes Care 24 (suppl 1):S44–49, 2001 3. American Diabetes Association: Clinical practice recommendations 2001, preventive foot care in patients with diabetes mellitus [position statement]. Diabetes Care 24 (suppl 1):S56–57, 2001 4. American Diabetes Association: Clinical practice recommendations 2001, report of the expert committee on the diagnosis and classification of diabetes mellitus [position statement]. Diabetes Care 24 (suppl 1):S1–20, 2001 5. American Diabetes Association: Clinical practice recommendations 2001, standards of medical care for patients with diabetes mellitus [position statement]. Diabetes Care 24 (suppl 1):S33–43, 2001 6. American Diabetes Association: Report of the expert committee on the diagnosis and classification of diabetes mellitus [position statement]. Diabetes Care 24 (suppl 1):S5–S20, 2001



7. Atkinson MA, Maclaren NK: The pathogenesis of insulin dependent diabetes. N Engl J Med 331:1428–1436, 1994 8. Barnett AH, Eff C, Leslie RD, et al: Diabetes in identical twins. A study of 200 pairs. Diabetologia 20:87–93, 1981 9. Beck-Neilsen H, Groop LC: Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin dependent diabetes mellitus. J Clin Invest 94:1714, 1994 10. Bell GI, Froguel P, Nishi S, et al: Mutations of the human glucokinase gene and diabetes mellitus. Trends Endocrinology Metabolism 4:86, 1993 11. Binder C, Lauritzen T, Faber O, et al: Insulin pharmacokinetics. Diabetes Care 7:188, 1984 12. Boden G, Chen X: Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 96:1261, 1995 13. Cantor AB, Krischer JP, Cuthertson DD, et al: Age and family relationship accentuate the risk of IDDM in relatives of patients with insulin dependent diabetes. J Clin Endocrinol Metab 80:3739–3743, 1995 14. Clark CM Jr, Lee AD: Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 332:1210–1217, 1995 15. Davies JL, Kawaguchi Y, Bennet ST, et al: A genome wide search for human type 1 diabetes susceptibility genes. Nature 371:130, 1994 16. DeFronzo RA: Pathogenesis of type 2 diabetes; metabolic and molecular implications for identifying diabetes genes. Diabetes Review 5:177–269, 1997 17. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993 18. Dietrich ML, Dolnicek TF, Rayburn WR: Gestational diabetes screening in a private, Midwestern American population. Am J Obstet Gynecol 156:1403–1408, 1987 19. Duck SC, Weldon VU, Pagliara AS, et al: Cerebral edema complicating therapy for diabetic ketoacidosis. Diabetes 25:111–115, 1976 20. Ritz E, Orth SR: Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 341:1127–1132, 1999 21. Ferris FL III, Davis MD, Aiello LM: Treatment of diabetic retinopathy. New Eng J Medicine 341:667–678, 1999 22. Huang W, Connor E, Dela Rosa T, et al: Although DR3-DQB1 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB110302 haplotype is implicated only in beta cell autoimmunity. J Clin Endocrinol Metab 81:1–5, 1996 23. Kahn CR: Banting Lecture: Insulin action, diabetogenes and the cause of type 2 diabetes. Diabetes 43:1066, 1994 24. Kaprio J, Tuomilheto J, Koskenvuo M, et al: Concordance of type 1 and type 2 diabetes mellitus in a population based cohort of twins in Finland. Diabetologia 35:1060, 1992 25. Lebovitz HT. Diabetic ketoacidosis. Lancet 345:767–772, 1995 26. Levey AS, Adler S, Caggiula AW, et al: Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 27:652–663, 1996 27. Lucas MJ, Lowe TW, Bowe L, et al: Class A1 gestational diabetes: A meaningful diagnosis? Obstet Gynecol 82:260–265, 1993 28. Makimattila S, Fineman MS, Yki-Jarvinen H: Deficiency of total and nonglycosylated amylin in plasma characterizes subjects with impaired glucose tolerance and type 2 diabetes. J Clin Endocrinol Metab 85:2822, 2000 29. Marquette GP, Klein VR, Niebyl JR: Efficacy of screening for gestational diabetes. Am J Perinatol 2:7–14, 1985 30. Harris MI: Summary: Diabetes in America ed 2. NIM Publication n095–1468 National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, 1995 31. Metzger BE, Coustan DR: Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 21 (suppl 2):B161–B167, 1998



32. Delaney MF, Zisman A, Kettyle WM: Diabetic ketoacidosis and hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am 29:683–705, 2000 33. Moller DE, Filer JS: Insulin resistance–mechanisms, syndromes and implications. N Engl J Med 325:938, 1991 34. Nathan DM: Long term complications of diabetes mellitus. N Engl J Med 328:1676– 1685, 1993 35. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039–1057, 1979 36. Newman B, Selby JV, Slemenda C, et al: Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30:763–738, 1987 37. Pan XR, Li GW, Hu YH, et al: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT Study. Diabetes Care 20:537, 1997 38. Paolisso G, Tataranni PA, Foley JE, et al: A high concentration of fasting plasma nonesterified fatty acids is a risk factor for the development of type 2 DM. Diabetologia 38:1213, 1995 39. DeFronzo RA: Pharmocologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281–303, 1999 40. Redondo MJ, Rewers M, Yu L, et al: Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: Prospective twin study. BMJ 318 March 698–702, 318–698, 1999 41. Roder ME, Dinese B, Hartling SG, et al: Intact proinsulin and beta-cell function in lean and obese subjects with and without type 2 diabetes. Diabetes Care 22:609, 1999 42. Szopa TM, Titchener PA, Portwood ND, et al: Diabetes mellitus due to viruses–Some recent developments. Diabetologia 40:53, 1997 44. Torjesen PA, Birkeland KI, Anderssen SA, et al: Lifestyle changes may reverse development of the insulin resistance syndrome. The Oslo Diet and Exercise Study: A randomized trial. Diabetes Care 20:26, 1997 45. UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 46. UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998 47. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 317:703–713, 1998 48. University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients adult-onset diabetes. Diabetes 19 (suppl 2):747– 830, 1970 49. Walston J, Silver K, Bogardus C, et al: Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the ␤-adrenergic-receptor gene. N Engl J Med 333:343, 1995 50. Wei M, Gibbons LW, Kampert JB, et al: The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men. Ann Intern Med 130:89, 1999 51. Wei M, Gibbons LW, Kampert JB, et al: Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med 132:605, 2000 52. Weyer C, Bogardus C, Mott DM, et al: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104:787, 1999 53. Widen E, Lehto M, Kanninen T, et al: Association of a polymorphism in the ␤adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 333:343, 1995 54. Wilding JP, Khandan-Nia N, Bennet WM, et al: Lack of acute effect of amylin on insulin sensitivity during hyperinsulinemic euglycemic clamp in humans. Diabetologia 37:166, 1994



55. World Health Organization: Diabetes Mellitus: Report of a WHO Study Group. Geneva, World Health Organization, 1985 56. Zimmert PZ, Tuomi T, Mackay R, et al: Latent autoimmune disease of the adult: The role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabetic Medicine 11:299–303, 1994 57. Zinman B, Zuniga-Guajardo S, Kelly D: Comparison of the acute and long-term effects of exercise on glucose control in type 1 diabetes. Diabetes Care 7:515, 1984 Address reprint requests to Dara P. Schuster Division of Endocrinology The Ohio State University Hospitals 491 McCampbell Hall 1581 Dodd Drive Columbus, OH 43205–2696 e-mail: [email protected]