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

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

Charles A. Reasner

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)


Microvascular Complications in Diabetes

Diabetic retinopathy

Leading cause of blindness in adults in the United


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


ESRD = end-stage renal disease.


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 2(11) represents the earliest demonstrable abnormality in glucose homeostasis in persons who are destined to develop type 2 diabetes mellitus later in life (Table 3).


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)


Fasting plasma glucose [greater than or equal]126 mg per dL

(7.0 mmol per L)


Postprandial glucose [greater than or equal]200 mg per dL

(11.1 mmol per L)


Random glucose [greater than or equal]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.


Progression of Type 2 Diabetes Mellitus

Factors Stage 1 (NGT)

HbA1c (%) [less than] 5.5

FPG (mg/dL) [less than] 110 (6.1 mmol per L)

Insulin resistance Moderate

Insulin levels [currency][currency][currency][*]

Treatment Diet + exercise

Factors Stage II (IGT/IFG)

HbA1c (%) 5.5 to 6.1

FPG (mg/dL) 110 to 125 (6.1 to

6.9 mmol per L)

Insulin resistance Moderate

Insulin levels [currency][currency]

Treatment Diet + exercise

Stage III (type 2

Factors diabetes mellitus)

HbA1c (%) 6.2 to 7.5

FPG (mg/dL) 126 to 160 (7.0 to

8.9 mmol per L)

Insulin resistance Moderate

Insulin levels [currency] or NL

Treatment Insulin sensitizer

Stage IV (type 2

Factors diabetes mellitus)

HbA1c (%) 7.6 to 10.0

FPG (mg/dL) 161 to 240 (8.9 to

13.3 mmol per L)

Insulin resistance Moderate-severe

Insulin levels O or OO

Treatment Insulin sensitizers

+ insulin secretagogue

Stage V (type 2

Factors diabetes mellitus)

HbA1c (%) [greater than] 10.0

FPG (mg/dL) [greater than] 240 (13.3 mmol

per L)

Insulin resistance Severe

Insulin levels OOO

Treatment 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., [currency] = increased; O = 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 Trial(6) and the United Kingdom Prospective Diabetes Study (UKPDS)(7,8) have demonstrated that the glycosylated hemoglobin (HbA1c) 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.

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 4(15) and are reviewed in detail in the accompanying article by Feinglos and Luna.(16)


Oral Agents in the Treatment of Type 2 Diabetes Mellitus

Insulin secretagogues



Insulin sensitizers

Metformin (Glugophage)



Alpha glucosidase inhibitors

Information from DeFronzo RA. Pharmacologic therapy for

type 2 diabetes mellitus. Ann Intern Med 1999;131:281-303.

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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.


(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;37:948-52.

(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.

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.

COPYRIGHT 2001 American Academy of Family Physicians

COPYRIGHT 2001 Gale Group