Editorials

Treatment of Type 2 Diabetes Mellitus: A Rational Approach Based on Its Pathophysiology

CHARLES A. REASNER, M.D.
RALPH A. DEFRONZO, M.D.
University of Texas Health Science Center
at San Antonio
San Antonio, Texas

See article in this issue.

Type 2 diabetes (formerly known as non­ insulin-dependent diabetes) results from progressive beta-cell failure superimposed on long-standing insulin resistance.^1,2 The insulin resistance is associated with a cluster of metabolic abnormalities, including central obesity, hypertension, dyslipidemia (elevated plasma triglycerides, low high-density lipoprotein [HDL] cholesterol levels and postprandial hyperlipidemia), hyperinsulinemia and elevated plasminogen activator inhibitor-1 (PAI-1) levels, which collectively increase the risk of developing macrovascular disease.^3,4

In the United States, approximately 20 to 25 percent of the population is insulin resistant.⁵ While many of these persons will not become diabetic, they are at increased risk of heart attack or stroke. Diabetes is diagnosed if the fasting blood glucose level is 126 mg per dL (7.0 mmol per L) or higher, or if a random glucose reading is 200 mg per dL (11.1 mmol per L) or higher. It is well established that hyperglycemia, if inadequately controlled, is responsible for the development of microvascular complications, including retinopathy, nephropathy and neuropathy^6-8 (Table 1). While this editorial focuses specifically on the treatment of hyperglycemia, optimal treatment of the diabetic patient must address each component of the insulin resistance syndrome.^3,4

TABLE 1 Microvascular Complications in Diabetes Diabetic retinopathy Leading cause of blindness in adults in the United States 24,000 new cases of blindness every year (66 new cases each day) Diabetic nephropathy Leading cause of ESRD in the United States 27,581 new cases of ESRD every year (75 new cases each day) Diabetic neuropathy Very common in both type 1 and type 2 diabetes Present in 10 percent of patients at the time of diagnosis ESRD = end-stage renal disease.

TABLE 2 Key Glycemic Levels Normal fasting glucose 65 to 109 mg per dL (3.6 to 6.0 mmol per L) Impaired fasting glucose 110 to 125 mg per dL (6.1 to 6.9 mmol per L) Impaired glucose tolerance 2 hours post OGTT of 140 to 199 mg per dL (7.8 to 11.0 mmol per L) Diabetes   Fasting plasma glucose >=126 mg per dL (7.0 mmol per L)     or     Postprandial glucose >=200 mg per dL (11.1 mmol per L)     or     Random glucose >=200 mg per dL (11.1 mmol per L) with symptoms OGTT = oral glucose tolerance test. Information from Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

Pathophysiology

Hyperglycemia in type 2 diabetes is the result of two major abnormalities: (1) insulin resistance in skeletal muscle and the liver, and (2) a progressive decline in insulin production by the pancreas.^1,2 Insulin resistance results from as yet unknown genetic defects combined with environmental factors--predominantly obesity and physical inactivity. Early in the natural history of type 2 diabetes, the insulin-resistant, normoglucose tolerant person compensates by secreting an excessive amount of insulin.^9,10 Hyperglycemia (i.e., impaired glucose tolerance and eventual overt diabetes) results when the pancreas can no longer secrete sufficient amounts of insulin to offset the insulin resistance in the peripheral muscle and hepatic tissues.^1,2

In patients with type 2 diabetes, both skeletal muscle and the liver are resistant to insulin.^1,2 Following a typical meal, the majority (approximately 70 percent) of ingested glucose is taken up and disposed of by muscle tissue.^1,2 Insulin resistance in muscle leads to postprandial hyperglycemia and impaired glucose tolerance--two-hour plasma glucose of 140 to 199 mg per dL (7.8 to 11.0 mmol per L). Table 2¹¹ represents the earliest demonstrable abnormality in glucose homeostasis in persons who are destined to develop type 2 diabetes mellitus later in life (Table 3).

TABLE 3 Progression of Type 2 Diabetes Mellitus Factors Stage 1 (NGT) Stage II (IGT/IFG) Stage III (type 2 diabetes mellitus) Stage IV (type 2 diabetes mellitus) Stage V (type 2 diabetes mellitus) HbA1c (%) <5.5 5.5 to 6.1 6.2 to 7.5 7.6 to 10.0 >10.0 FPG (mg/dL) <110 (6.1 mmol per L) 110 to 125 (6.1 to 6.9 mmol per L) 126 to 160 (7.0 to 8.9 mmol per L) 161 to 240 (8.9 to 13.3 mmol per L) >240 (13.3 mmol per L) Insulin resistance Moderate Moderate Moderate Moderate-severe Severe Insulin levels * or NL or Treatment Diet + exercise Diet + exercise Insulin sensitizer Insulin sensitizers + insulin secretagogue Insulin sensitizers + insulin NGT = normal glucose tolerance; IGT = impaired glucose tolerance; IFG = impaired fasting glucose; HbA1c = glycosylated hemoglobin; FPG = fasting plasma glucose; NL = normal. *--The number of arrows indicates the magnitude of the change in insulin secretion (i.e., = increased; = decreased).

Although the liver also is resistant to the action of insulin, hyperinsulinemia (which represents a compensatory response of the pancreatic beta cells to offset the insulin resistance) in persons with impaired glucose tolerance is sufficient to prevent hepatic glucose output and thus prevents the fasting plasma glucose concentration from rising above normal. This is explained by the observation that it takes three to four times as much insulin to stimulate glucose uptake into muscle as it does to inhibit hepatic glucose production.^1,2 With time, however, the hepatic insulin resistance worsens, and hepatic glucose production increases, leading to a small increase in the fasting plasma glucose concentration.¹² Such persons are characterized as having impaired fasting glucose--plasma glucose concentration of 110 to 125 mg per dL (6.1 to 6.9 mmol per L). Eventually, the secretion of insulin begins to decline, leading to a marked excess in production of glucose by the liver throughout the sleeping hours, and this results in overt fasting hyperglycemia--fasting plasma glucose level of 126 mg per dL or more (Table 2).¹¹

This sequence of pathophysiologic derangements explains why postprandial hyperglycemia (insulin resistance in muscle) often is present for several years before the development of fasting hyperglycemia (insulin resistance in the liver). A rational approach to the treatment of hyperglycemia logically follows the pathogenesis of type 2 diabetes and a recognition of where the patient falls in the natural history of the disease.

Five stages have been defined in the progression from normal glucose tolerance to impaired glucose tolerance to fasting hyperglycemia and, eventually, to overt diabetes with severe insulin resistance and decreased insulin secretion (Table 3).

Treatment Strategy

Optimal therapy in a patient with type 2 diabetes should correct all of the metabolic defects that are present. Because beta-cell failure is progressive, treatment interventions will have to be continuously monitored and advanced. Both the Diabetes Control and Complications Trial⁶ and the United Kingdom Prospective Diabetes Study (UKPDS)^7,8 have demonstrated that the glycosylated hemoglobin (HbA_1c) level must be reduced to less than 7 percent to minimize or prevent the development of microvascular complications. Achievement of ideal body weight and maintenance of an exercise regimen (i.e., interventions that improve insulin resistance) are the cornerstones of therapy (stage II) and should be initiated before the person displays overt diabetes mellitus. Weight loss and exercise have been shown to delay the onset of diabetes^13,14 and will enhance pharmacologic interventions when they become necessary.

TABLE 4 Oral Agents in the Treatment of Type 2 Diabetes Mellitus Insulin secretagogues Sulfonylureas Meglitinides Insulin sensitizers Metformin (Glugophage) Thiazolidinediones Others Alpha glucosidase inhibitors Information from DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281-303.

Oral Agents

Therapy with oral agents should be initiated when the patient's blood glucose levels reach the threshold for diagnosing diabetes (Table 2).¹¹ A fasting glucose level of 126 mg per dL or more and a postprandial glucose level of 200 mg per dL or more have been shown to be associated with a significant increase in the development of microvascular complications.¹¹ The currently available oral agents, based on their mechanism of action, are shown in Table 4¹⁵ and are reviewed in detail in the accompanying article by Feinglos and Luna.¹⁶

Because the dominant defect in the early stages of diabetes is insulin resistance,^1,2 we recommend initiating therapy with an insulin sensitizer in patients with HbA_1c levels of 7.5 to 8.0 percent or less (stage III).¹⁵ We prefer to initiate therapy in these persons with metformin (Glucophage) because it is more effective in lowering the blood glucose concentration than other insulin sensitizers and has beneficial effects on many components of the insulin resistance syndrome.^15,17 It is likely that metformin's ability to cause weight loss, improve diabetic dyslipidemia and lower insulin and PAI-1 levels was responsible for the reduction in macrovascular complications (heart attack and stroke) in the UKPDS⁷ in the cohort initially treated with metformin.

Failure to achieve an HbA_1c of less than 7 percent while taking an insulin sensitizer suggests the presence of more advanced disease, with significant beta-cell failure. Such persons require the addition of an insulin secretagogue (stage IV).¹⁵ Combining an insulin secretagogue (sulfonylureas or meglitinides) with an insulin sensitizer (metformin or thiazolidinediones) provides a completely additive reduction in blood glucose level.¹⁵ Patients who present in stage III with an HbA_1c of more than 8.5 to 9.0 percent often benefit by initiating therapy with both an insulin sensitizer and an insulin secretagogue. Glucovance, a combination metformin/glyburide preparation, has recently been approved for use as initial therapy in patients with type 2 diabetes.

A third drug is required if the HbA_1c exceeds 7 percent despite treatment with an insulin secretagogue and an insulin sensitizer. The choice of a third agent (i.e., a thiazolidinedione or insulin) depends on the individual patient's ability to secrete insulin.¹⁵ If significant residual insulin secretory capacity remains, addition of a second insulin sensitizer (i.e., metformin or a thiazolidinedione) may be highly effective. In our experience, obese patients who have been diagnosed with diabetes for fewer than 10 years often maintain the ability to secrete significant amounts of insulin and respond well to triple oral agent therapy (metformin, insulin secretagogue, thiazolidinedione) (stage IV).¹⁵

Conversely, nonobese patients with long-standing diabetes (more than 10 years) are more likely to be absolutely insulinopenic and require exogenous insulin treatment (stage V).¹⁵ In these patients, we recommend initiating therapy with a long-acting insulin (i.e., NPH or glargine insulin) at bedtime and discontinuing the oral insulin secretagogue, while maintaining therapy with an insulin sensitizer to treat the underlying insulin resistance. We prefer to use metformin because it blunts the weight gain observed with insulin therapy and because of the UKPDS⁸ results, which reveal a beneficial effect of metformin in reducing heart attack and stroke.

If the bedtime insulin dosage exceeds 50 to 60 units per day, the patient should be placed on a mixed-split insulin regimen (NPH insulin twice daily or glargine insulin plus regular insulin two to three times daily). Treatment of the other components of the insulin resistance syndrome,^3,4 including obesity, hypertension, dyslipidemia and clotting factor abnormalities is also essential if we are to eliminate the increased risk of macrovascular complications in these patients.

Ralph A. DeFronzo, M.D., is professor of medicine and chief of the Diabetes Division at the University of Texas Health Science Center at San Antonio, San Antonio, Texas. Dr. DeFronzo is also deputy director of the Texas Diabetes Institute, San Antonio.

Charles A. Reasner, M.D., is professor of medicine in the Diabetes and Endocrine Divisions at the University of Texas Health Science Center at San Antonio. Dr. Reasner is also medical director of the Texas Diabetes Institute.

Address correspondence to Ralph A. DeFronzo, M.D., Diabetes Division, University of Texas Health Science Center at San Antonio, 7700 Floyd Curl Dr., San Antonio, TX 78229. Reprints are not available from the authors.

REFERENCES

1. DeFronzo RA. Lilly lecture. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37:667-87.
2. DeFronzo RA. Pathogenesis of type 2 diabetes. Diabetes Rev 1997;4:177-269.
3. Reaven GM, Laws A. Insulin resistance, compensatory hyperinsulinemia, and coronary heart disease. Diabetologia 1994;37:948­52.
4. DeFronzo RA. Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic web. J Cardiovasc Pharmacol 1992;20(suppl 1):S1-16.
5. Diamond MP, Thornton K. Connolly-Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol Investig 1995;2:708-15.
6. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.
7. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. 1998;352:837-53.
8. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854-65.
9. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet 1989;1:1356-9.
10. Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992; 41:1575-86.
11. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.
12. DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989;38:387-95.
13. Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia 1991;34:891-8.
14. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44.
15. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281-303.
16. Luna B, Feinglos MN. Oral agents in the management of type 2 diabetes mellitus. Am Fam Physician 2001;63:1747-56,1759-60.
17. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:541-9.

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Finding Guidance Amid Uncertainty of ADHD Diagnosis

AMER SHAKIL, M.D.
University of Texas Southwestern
Medical Center at Dallas
Dallas, Texas

See article in this issue.

The idea of collaborative care has been captured in the saying "It takes a whole village to raise a child." This is also true with families who are raising children with attention-deficit/hyperactivity disorder (ADHD). This message echoes throughout the new ADHD clinical guidelines discussed by Herrerias and colleagues¹ in this issue of American Family Physician.

The National Institutes of Health (NIH) issued a statement at the end of a Consensus Development conference in November 1998, stating that "ADHD has remained controversial in many public and private sectors." The panel recognized that "we do not have an independent valid test for ADHD, and there is no data to indicate whether ADHD is due to a brain malfunction." Recommendations by the panel were "further efforts to validate the disorder," that "basic research is needed to better define ADHD," and that "a more consistent set of diagnostic procedures and practice guidelines is of utmost importance."²

In practice, it is not uncommon to see children in whom symptoms of ADHD are not clearly distinguishable from normal variations in temperament. Temperament research shows that there is wide variation in the activity level of normal children, and we do not have consistent pathologic changes or structural, functional or chemical markers to guide diagnosis. Diagnostic questionnaires tend to be highly subjective and impressionistic, adding to the complexity of acting as the family and child's advocate. However, an advantage of ADHD labeling is that it may remove the blame from parents and schools, and help such children get needed services and justification of medicine use.

Clinical practice guidelines summarized by Herrerias and colleagues¹ are the first step toward using evidence-based criteria to diagnose ADHD. Recorded prevalence rates for ADHD vary substantially, partly because of changing diagnostic criteria over time,³ and partly because of variations in ascertainment in different settings and the frequent use of referred samples to estimate rates. Practitioners vary greatly in the degree to which they use criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) to diagnose ADHD. Several recommendations were made to establish evidence-based criteria for ADHD. One important recommendation was that the DSM-IV work group incorporate a pediatrician, a family physician, or both, in their panel.

Public interest in ADHD has increased along with debate in the media concerning the diagnostic process and treatment strategies.⁴ Concern has been expressed about the overdiagnosis of ADHD by pointing to the several-fold increase in prescriptions for stimulant medication among children during the past decade.⁵ There is little objective evidence, however, of widespread overdiagnosis of ADHD or of widespread over-prescription of methylphenidate (Ritalin) by physicians.⁶

Screening for school performance at all office visits for school-aged children may improve early detection of ADHD. Screening can be done by asking questions regarding any concern of teachers or parents about a child's behavior or any learning issues noted by them. Yet even this step leaves the clinician at a loss when dealing with children who do not have a clear-cut diagnosis or when diagnostic criteria may actually be inappropriate for a particular child.

Finally, ADHD is a syndrome and does not always present in a classic manner. When ADHD is present, the impact on the life of the child and the family can be quite dramatic, demanding that practitioners intervene with the entire family. In one case, for example, parents reported that the ordeal has taught them how to be patient in raising their child. In the words of the great mystical poet Rumi⁷:

The core of every fruit
	is better than its rind.
Regard the body as the rind,
	and the human spirit the core.

Amer Shakil, M.D., is an assistant professor at the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

Address correspondence to Amer Shakil, M.D., St. Paul Family Practice Residency Program, 5550 Harvest Hill Rd., Ste. 100, Dallas, TX 75230.

REFERENCES

1. Herrerias CT, Perrin JM, Stein MT. The child with ADHD: the AAP clinical practice guideline. Am Fam Physician 2001;63:1803-10,1811.
2. Carey WB. Problems in diagnosing attention and activity. Pediatrics 1999;103:664-6.
3. American Psychiatric Association. Diagnostic and statistical manual for mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association, 1994.
4. Gibbs N. Latest on Ritalin. Time 1998;152:86-96.
5. Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder in the 1990s. Pediatrics 1996;98:1084-8.
6. Goldman LS, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA 1998;279:1100-7.
7. Mabey J, compiler. Rumi: a spiritual treasury. Boston: Oneworld Publications, 2000.

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Where Family Physicians Dare

DONALD E. PATHMAN, M.D., M.P.H.
University of North Carolina
Chapel Hill, North Carolina

See article in this issue.

Sometimes data are compelling. In this issue of American Family Physician, researchers at the AAFP's Robert Graham Center: Policy Studies in Family Practice and Primary Care demonstrate convincingly family physicians' unique role in promoting access to health care.¹ In a straightforward and clever approach, researchers at the center analyzed national physician and population data for 1995 to show how geographic access to physicians would suffer if there were no family physicians. Without family physicians, 1,332 new counties would drop below the threshold of one primary care physician per 3,500 population. Below this threshold, they would earn automatic designation as whole-county Health Professional Shortage Areas (HPSAs), thereby tripling the 784 counties now designated. If, instead, all other primary care specialists were eliminated, only 176 new counties would earn HPSA designations.

As the center's report states, the unique locations of family physicians' practices underlie these striking findings. Unlike any other specialists, family physicians distribute themselves wherever people are found, from the smallest rural to largest urban areas.^2,3 In contrast, subspecialists cluster near larger medical centers and close to the regional technologies important to their work, and these centers tend to be in larger and wealthier urban settings.⁴ Even other generalist disciplines are distributed less democratically than family physicians, in part because a practice limited by patients' ages or gender requires a larger population base.^4,5

Family physicians locate to match the U.S. population for several reasons. Some family physicians are altruists, willing to commit their families and careers to meet communities' needs.⁶ Others simply find acceptable employment where physicians of other specialties do not: the temperament and broad training of family physicians enable them to work comfortably in settings with few consultants and little technology.⁴ Still others actually prefer to practice in settings far from other physicians, thereby avoiding the inter-specialty turf struggles common in more populated medical communities. Also, many family physicians hail from smaller towns and value the life and work they find there.⁷ Whatever the reasons, family physicians often settle where they are needed most and then succeed there. For these reasons, the National Health Service Corps and similar state-run support-for-service-programs have deemed family physicians their preferred specialists.^8,9

Even in the urban and rural areas where physician counts suggest adequacy, local subpopulations often have unmet needs. In these frequent situations where existing community resources do not meet the needs of certain groups--most often children, the elderly, pregnant women, the mentally ill, and those with medical emergencies--family physicians often respond by adjusting the content of their work. They will assume care for nursing home patients, add or drop hospital care and broaden the range of medical conditions they manage if the need is there. Their broad, unique training allows them to substitute for physicians from a range of other subspecialties. The responsive plasticity of family physicians' work has not been adequately documented, but it is substantiated by evidence such as the tendency for those in areas with fewer obstetricians to practice obstetrics.¹⁰

Family physicians' unique contributions to health care access stem from the breadth of their training, adaptability of their work and a sense of social responsibility. If medicine was a baseball team, family physicians would be its much-valued utility player.

Donald E. Pathman, M.D., M.P.H., is associate professor and research director of family medicine, and senior research fellow at Cecil G. Sheps Center for Health Services Research at the University of North Carolina, Chapel Hill, N.C.

Address correspondence to Donald E. Pathman, M.D., M.P.H., Department of Family Medicine, University of North Carolina, Chapel Hill, CB #7595, Chapel Hill, NC 27599.

REFERENCES

1. Robert Graham Center: Policy Studies in Family Practice and Primary Care. The United States relies on family physicians unlike any other specialty. Am Fam Physician 2001;63:1669.
2. Council on Graduate Medical Education. Improving access to health care through physician workforce reform: directions for the 21st century. Third Report. U.S. Department of Health and Human Services, Public Health Service, Health Resources and Services Administration, October 1992.
3. Council on Graduate Medical Education. Physician distribution and health care challenges in rural and inner-city areas. Tenth Report. U.S. Department of Health and Human Services, Public Health Service, Health Resources and Services Administration, February 1998; DHHS publication no. 97-44.
4. Rosenblatt RA, Hart LG. Physicians and rural America. In: Rural health in the United States. Ricketts TC, ed. New York: Oxford University Press, 1999.
5. Randolph GD, Pathman DE. Trends in the rural-urban distribution of general pediatricians. Pediatrics 2001;107:e18.
6. Madison DL. Medical school admission and generalist physicians: a study of the class of 1985. Acad Med 1994;69:825-31.
7. Gorenflo DW, Ruffin MT, Sheets KJ. A multivariate model for specialty preference by medical students. J Fam Pract 1994;39:570-6.
8. National Health Services Corps. Proposed strategies for fulfilling primary care manpower needs. A white paper. Unpublished document prepared for the NHSC National Advisory Council, dated October 6,1989.
9. Pathman DE, Taylor DH, Konrad TR, King TS, Harris T, Henderson TM, et al. State scholarship, loan forgiveness, and related programs: the unheralded safety net. JAMA 2000;284:2084-92.
10. Pathman DE, Tropman S. Obstetrical practice among new rural family physicians. J Fam Pract 1995;40: 457-64.

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