0095-4543/99 $8.00 + .00
`
`Barbara A. Ramlo- Halsted, MD, and Steven V. Edelman, MD
`
`Effective therapy of type 2 diabetes has been a challenge. Patients
`with type 2 diabetes face a chronic, progressive disease that leads to com-
`plications that profoundly affect both quality of life and longevity. Ad-
`ditionally,
`the clinician is challenged with a heterogeneous disorder that
`has a wide spectrum of complications that progress and responses to treat-
`ment that vary with each individual patient over time. The goal of this
`article is to acquaint the primary care provider with the pathogenesis of
`type 2 diabetes and how this condition progres~es from an early asymp-
`tomatic stage with insulin resistance to mild postprandial hyperglycemia
`to frank diabetes requiring pharmacologic intervention. Understanding
`this natural history of type 2 diabetes helps guide the clinician in for-
`mulating an effective treatment regimen that reflects the pathologic dif-
`ferences between the various stages of this disease. The most successful
`treatment strategies hinge on this key point: the optimal regimen (par-
`ticularly regarding medication choices) will change for each individual
`patient as the diabetes progresses. Clinicians now are able to make more
`sophisticated and effective management plans based on current knowl-
`
`This work was supported by a Career Development Grant from the Veterans Admin-
`istration, San Diego, California, awarded to Barbara A. Ramlo-Halsted, MD.
`
`From the Division of Endocrinology and Metabolism, University of California, San Diego;
`and the Veterans Affairs Medical Center, San Diego, California
`
`PRIMARY CARE
`
`VOLUME 26 .NUMBER 4 .DECEMBER 1999
`
`771
`
`DIABETES
`
`AstraZeneca Exhibit 2064
`Mylan v. AstraZeneca
`IPR2015-01340
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`Page 1 of 19
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`RAMLO-HALSTED & EDELMAN
`
`edge gained from large clinical studies and the ever-growing number of
`medications available for the treatment of type 2 diabetes.
`The term impaired glucose tolerance (IGT) or prediabetes was first
`coined in 1979 by the World Healtl.' Organization (WHO) and The Na-
`tional Diabetes Data Group (NDDG) to replace the terms borderline, chem-
`ical, and asymptomatic diabetes mellitus. In 1997, the American Diabetes As-
`sociation's (ADA) Expert Committee recommended the following criteria
`for IGT: a normal fasting plasma glucose (less than 126 mg/ dL) and a
`plasma glucose of 140 mg/ dL or greater, but less than 200 mg/ dL 2 hours
`after a 75 g oral glucose challenge. T~is stage of mild postprandial hy-
`perglycemia
`is both an important area of clinical research and an ex-
`tremely useful marker of patients at risk for developing of type 2 diabetes.
`Patients with IGT may benefit from timely patient education and perhaps
`even more aggressive forms of intervention such as diet, exercise, or med-
`ication. Clinical research interests have expanded beyond developing new
`ways to treat type 2 diabetes. Major efforts now are being made to deter-
`mine who is at the highest risk for diabetes and to formulate cost-effective
`prevention strategies aimed at these individuals.
`
`PATHOGENESIS OF IMPAIRED GLUCOSE TOLERANCE
`AND TYPE 2 DIABETES MELLITUS
`
`Type 2 diabetes mellitus is a heterogeneous disorder; three basic met-
`abolic defects characterize the disease: insulin resistance, an insulin secre-
`tory defect that is not autoimmune mediated, and an increase in glucose
`production by the liver. The cause of these metabolic defects, and therefore
`the cause of type 2 diabetes, largely is unknown. Clearly, type 2 diabetes
`has a strong genetic component and is found more frequently in certain
`families and ethnic minority groups such as Hispanics, African Ameri-
`cans, Pacific Islanders, and Native American Indians. Furthermore, twin
`studies have shown that monozygotic twins have at least a twofold greater
`concordance in the incidence of diabetes compared with dizygotic twins.3O
`Great effort has been made to find single or clustered genetic defects com-
`mon to diabetics. The relative failure in finding candidate genes that lead
`to type 2 diabetes most certainly suggests that the disease is extremely
`heterogeneous, with probably multigenetic defects. Furthermore, many
`acquired factors have been identified
`that also playa role in the patho-
`genesis of the disease. Figure 1 depicts the sequence of events that occur
`before frank diabetes develops and the potential role of these genetic and
`acquired factors in the basic metabolic defects that characterize type 2
`diabetes.
`little headway has been made in attributing any specific
`Although
`underlying genetic defect to type 2 diabetes, considerable information is
`available on the underlying metabolic defects. As mentioned above, the
`defects are a triad of insulin resistance, ~-cell dysfunctio~, and increased
`
`Page 2 of 19
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`THE NATURAL HISTORY OF TYPE 2 DIABETES
`
`773
`
`~-cell failure
`
`I
`
`Type2+0iabetes
`
`I
`
`to type 2 diabetes. The etiologic sequence of the development of
`Figure 1. Progression
`Type 2 diabetes. FFA-free fatty acid.
`
`hepatic glucose production. Some controversy still exists as to whether
`insulin resistance or inadequate insulin secretion occurs first in the patho-
`genesis of diabetes; a general consensus, however, has emerged that in-
`sulin resistance is the primary defect in type 2 diabetes.9.33 Insulin resis-
`tance is characterized by a subnormal response to a given concentration
`of insulin.
`Insulin resistance is measured indir~ctly by a fasting insulin
`level (higher levels of insulin correspond to higher degrees of insulin re-
`sistance) or directly in a research setting using a euglycemic insulin-clamp
`technique.
`The cause of pancreatic p-cell dysfunction, the second metabolic de-
`fect that appears in type 2 diabetics, is still a focus of intense research and
`debate. Several key pieces of information on the specific p-cell defects in
`type 2 diabetes, however, are well characterized.22 Changes in the p-cell
`occur early in the pathogenesis of type 2 diabetes. In fact, in patients with
`insulin resistance, a measurable change occurs in the pulsatile secretory
`pattern of insulin release before diabetes or even IGT develop. The patho-
`genic and clinical relevance of this early defect is unclear. Later defects in
`glucose-stimulated
`insulin release occur that clearly playa
`role in the
`progression to diabetes and then continue to affect the course of diabetes
`itself. For example, the decline in insulin levels, and thus a decrease in
`insulin's
`inhibitory effects, allows for increased hepatic glucose produc-
`tion. Beta-cell exhaustion may be genetically mediated, termed prepro-
`grammed fi-cell failure, or result from hypothesized damage to the p-cell
`from chronic exposure to hyperglycemia (glucose toxicity model) or result
`from adverse affects of increased free fatty acids. Whatever the underlying
`causes and mechanisms it is clear that the full phenotypic expression of
`type 2 diabetes requires both insulin resistanc_e and p-cell dysfunction.
`
`~
`
`Page 3 of 19
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`RAMLQ-HALSTED & EDELMAN
`
`PROGRESSION OF IMPAIRED GLUCOSE TOLERANCE
`TO MILD TYPE 2 DIABETES
`
`The metabolic sequences that eventually lead to type 2 diabetes pre-
`cede the development of hyperglycemia by years or even decades. As
`shown in Figure 2, studies have shown that 20% of type 2 diabetics have
`retinopathy at the time of diagnosis, a percentage that increases linearly
`with the duration of diabetes. Epidemiologists have extrapolated this data
`to estimate that the onset of detectable retinopathy probably occurs an
`average of 6.5 years before the clinical diagnosis of diabetes. Diabetic ret-
`inopathy does not develop until hyperglycemia persists for several years
`and thus the true onset of type 2 diabetes often is more than 10 years
`before the clinical diagnosis.
`Insulin resistance, that is resistance to insulin's role in promoting glu-
`cose uptake by skeletal muscle and fat cells, is the initial metabolic defect.
`Figure 3 summarizes the natural history of this defect in the progression
`of IGT to frank type 2 diabetes. At first, the pancreatic ~-cell is able to
`compensate by increasing insulin levels, leading to hyperinsulinemia. This
`compensation is able to keep glucose levels normalized
`for a period of
`time (up to several years), but IGT develops with mild postprandial hy-
`
`80
`
`60
`
`40
`
`20
`
`0
`
`-10
`
`0
`
`5
`
`10
`
`15
`
`20
`
`Time Since Diagnosis of NIDMM (y)
`
`>.
`
`~0
`
`-
`
`0=
`OJ~
`oS
`.~
`
`.~
`
`=O
`
`J~OJ~
`
`Figure 2. The prevalence of retinopathy at thl
`olation of the data indicates the time at whicl
`diabetes often is several years before clinical I
`glycemia and microvascular and macrovascul;
`268, 1995; with permission.)
`
`time of diagnosis of type 2 diabetes. Extrap-h
`retinopathy first developed. Onset of type 2evidence
`of retinopathy. (From Klien R: Hyper-ar
`disease in diabetes. Diabetes Care 18:258-
`
`-6.5
`e
`
`Page 4 of 19
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`

`
`THE NATURAL HISTORY OF TYPE 2 DIABETES
`
`775
`
`Impaired Glucose Tolerance
`
`Frank Diabetes
`
`Severity of Diabetes
`
`Insulin resistance
`
`Hepatic glucose
`production
`
`Endogenous
`
`insulin
`
`I
`
`Postparndial blood
`sugar
`Fasting blood
`sugar
`
`Endogenous
`
`insulin I
`
`~
`Time (y)
`
`4-7 years
`
`to
`
`"
`
`Diagnosis
`of Diabetes
`
`Figure 3. Natural history of type 2 diabetes. The prediabetic state of impaired glucose toler-
`ance is characterized by increasing insulin resistance, compensatory hyperinsulinemia, and
`mild postprandial hyperglycemia.
`Initially, fasting blood glucose levels (FBG) are maintained
`in near normal ranges. The p-cell then begins to fail, resulting in higher postprandial glucose
`levels and, with further loss of insulin secretory capacity and impaired glucorecognition, FBG
`and hepatic glucose production increase.
`
`perglycemia. As insulin resistance worsens, more global defects in insulin
`secretion occur that result in increased hepatic glucose production. These
`defects together lead to further elevations in the fasting blood sugar. The
`ADA has encouraged the use of the term impaired fasting glucose (IFG),
`which is defined as having a fasting plasma glucose (FPG) level of 110
`mg/ dL or greater but less than 126 mg/ dL;2 to denote this stage. Clini-
`cally IFG and IGT represent a similar point along the continuum between
`normal glucose tolerance and frank diabetes: an essentially asymptomatic,
`but still potentially pathologic stage characterized by mild hyperglycemia.
`Both IGT and IFG serve as markers for those who are at greatest risk for
`developing type 2 diabetes.
`Numerous prospective and cross-sectional studies have determined
`the cumulative
`risk of developing
`type 2 diabetes once IGT is recog-
`nized.7,3O Table 1 summarizes many of these studies. Depending on the
`duration of follow-up and the ethnic group studied, prospective clinical
`
`:
`
`Page 5 of 19
`
`

`
`776
`
`RAMLO-HALSTED & EDELMAN
`
`Table 1. INCIDENCE OF TYPE 2 DIABETES IN PERSONS WITH IMPAIRED
`GLUCOSE TOLERANCE
`
`Mean Age
`(y)
`
`38
`32
`35-74
`44-55
`
`No. of
`Subjects
`51
`384
`75
`486
`
`Duration of
`Follow-upt
`(y)
`6.2
`3.3
`6.0
`2.5
`
`20-7420-74
`
`49
`25-64
`
`128211
`
`4.0
`4.0
`4.0
`8.0
`
`Average Annual
`Incidence
`of Type 2
`Diabetes* (%)
`
`4.0
`6.1
`5.1
`2.1
`
`8.7
`5.3
`12.6
`2.7
`
`Population
`with
`IGT
`
`Nauruans
`Pima Indians
`Maltese
`French
`Colorado
`Hispanics
`Non-Hispanic whites
`South African Indians
`San Antonio, TX
`Hispanics and Non-
`Hispanic whites
`
`*World Health Organization guidelines were used for the diagnostic criteria of IGT and type 2 dia-betes
`in each study.
`tDuration of follow up are mean values.
`Data from Rewers M, Hanuman RF: Risk factors for non-insulin-dependent diabetes. 111 Diabetes in
`America, ed. 2. National Institutes of Health, National Institutes of Diabetes, Digestive and Kidney Dis-
`eases (NHH Publication No. 95-1468, 1995)
`
`trials have shown that approximately one third of individuals with IGT
`progress to type 2 diabetes. The role of race and ethnicity in the incidence
`of progression to diabetes cannot be overemphasized. African Americans,
`Native American
`Indians, Hispanics, and Pacific Islanders all have a
`higher than average incidence of both IGT and type 2 diabetes. For ex-
`ample, the incidence of IGT is 17.6 per 1000 person-years in non-Hispanic
`whites and 32.6 per 1000 person-years in Hispanics. Furthermore,
`in a
`Colorado-based study, Hispanics with IGT had an 8.7% annual incidence
`of type 2 diabetes, whereas non-Hispanic whites with IGT had an inci-
`dence of 5.3% per year of diabetes.3o
`The progression from IGT to early type 2 diabetes is marked by a
`decrease in ~-cell function and thus a decline in insulin secretion (see Fig.
`3). It is the failure over time of the ~-cell to compensate for insulin resis-
`tance with hyperinsulinemia
`that marks the beginning of type 2 diabetes.
`So long as the pancreatic ~-cell is able to compensate for insulin resistance
`by increasing insulin production and secretion, glucose levels remain nor-
`mal or nealnormal. Eventually, the ~-cell begins to fail and insulin secre-
`tion falls, resulting in hyperglycemia. Eventual failure of the pancreatic
`~-cell has been a predictable abnormality leading to changes in a patient's
`response to various therapies.
`Two other additional pathophysiologic changes become manifest
`during the transition from IGT to type 2 diabetes. Insulin resistance be-
`comes more severe, a progression that may not be caused only by full
`expression of genetic defects, but also by acquired factors such as obesity,
`decreased physical activity, and aging. As discussed in more detail later
`
`Page 6 of 19
`
`

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`THE NATURAL HISTORY OF TYPE 2 DIABETES
`
`777
`
`and summarized in the box below, all of these factors have been identified
`epidemiologically as risk factors for type 2 diabetes and have the potential
`to be causally related to the appearance and progression of insulin resis-
`
`tance.8,9,10,14,29 The second change is. an increase in basal hepatic glucose
`production (HGP). Although early type 2 diabetes may be as asymptom-
`atic as the preceding stage of IGT, the degree of hyperglycemia is now
`severe enough to start the clock for the development of microvascular
`complications.
`
`Increased age
`Eth n icity (u rbanization / westernization)
`Hispanic, African American, Native American Indian, and Pacific
`Islander
`Family history of diabetes
`Central obesity (moderate and morbid)
`Sedentary
`lifestyle
`History of gestational diabetes
`Impaired glucose tolerance or impaired fasting glucose
`Elevated blood pressure*
`Elevated triglycerides*
`Low high density lipoprotein (HDL)
`*This has not proven to be an independent risk factor in all studies.
`
`PROGRESSION OF MilD TYPE 2 DIABETES MElliTUS
`TO INSULIN-REQUIRING TYPE 2 DIABETES MElliTUS
`
`Insulin resistance is the primary pathogenic insult underlying type 2
`diabetes and remains a factor throughout the natural history of the dis-
`ease, yet it is the changes in p-cell function that determines both the onset
`of frank diabetes and the progression of the disease once established. As
`outlined above, the transition
`from normal glucose tolerance to IGT is
`marked by hyperinsulinemia
`that reflects a quantitatively appropriate re-
`sponse on the part of the p-cell to insulin resistance and postprandial
`hyperglycemia. Over time however, the p-cell becomes refractory to glu-
`cose and although the cell continues to secrete supra physiologic amounts
`of insulin, a relative insulin deficiency develops and hyperglycemia wors-
`ens to the point of frank diabetes. Later, the p-cell's secr~tory capacity
`further declines, in terms of maximum secretory response, pulsatility, and
`overall plasma insulin levels.22 An absolute insulin deficiency develops
`and eventually the p-cell becomes unresponsive to interventions aimed at
`improving p-cell function such as insulin secretagogues (including sul-
`fonylureas). By this point in the disease process, the type 2 diabetic most
`likely requires exogenous insulin or multiple oral agents used in combi-
`nation to achieve adequate glucose control.
`.
`
`!t
`
`Page 7 of 19
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`

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`RAMLO-HALSTED & EDELMAN
`
`These stages in the natural history of type 2 diabetes are important
`to consider in choosing and modifying a treatment regimen. Different
`classes of antidiabetic agents appear to be effective at different stages. This
`concept has been demonstrated repeatedly in prospective clinical trials
`that determine the secondary failure rates for medications used in the
`treatment of type 2 diabetes. Failure of an intervention that was initially
`effective often indicates progression of the disease. The treatment plan
`must then be modified to regain glycemic control.
`Secondary failure rates in the use of sulfonylureas have been studied
`and these trials are particularly. useful in understanding
`the role ~-cell
`dysfunction plays in the progression of type 2 diabetes. One of these stud-
`ies was conducted as part of the United Kingdom Prospective Diabetes
`Study (UKPDS) (See article by Baldeweg and Yudkin elsewhere in this
`issue.)2S,32 In the UKPDS, over 5000 newly diagnosed type 2 diabetics were
`randomized to receive either chlorpropamide or glibenclamide (both sul-
`fonylureas), metformin, or insulin and were then followed
`for 11 years.
`Failure of treatment was prospectively defined as a fasting plasma glucose
`greater than 108 mg/ dL. The linear overall failure rate in the UKPDS of
`all treatment groups was an impressive 7% per year (Fig. 4). Previous
`smaller-scale studies have estimated failure rates of 1.4% to 5.6% per
`year.18 By the end of the ll-year study, well over 50% of subjects required
`additional
`therapy (Fig. 4). Those subjects with the lowest level of ~-cell
`function had the highest rate of treatment failure with sulfonylureas.
`These results support the general belief that sulfonylurea failure is caused
`by declining ~-cell function, not by an ill-defined effect of the medication
`itself. This study also found an accelerated rate of sulfonylurea failures
`among younger diabetics (i.e., subjects less than 54 years of age at the time
`of diagnosis) and among the morbidly obese (i.e., those individuals with
`a body mass index [BMI] of 30 kg/m2 or greater), compared with the
`moderately obese (i.e., those patients with a BMI between 25-30 kg/m2).
`Obesity and duration of diabetes clearly have an impact on ~-cell function,
`beyond their affects on insulin resistance and, therefore, impact response
`to antidiabetic therapy. The role of obesity in the natural history of Type
`2 diabetes is discussed in more detail later.
`Studies focused on secondary failure rates of therapeutic interven-
`tions can be very useful, but several caveats must be considered when
`trying to apply such studies to actual clinical practice. These studies use
`medication failure as an endpoint, whereas in the practical treatment of
`diabetes, therapeutic intervention
`is needed as soon as the medication
`becomes inadequate in achieving ideal glucose control. Microvascular and
`macrovascular complications begin to develop in patients with baseline
`fasting plasma glucose levels much lower than those values used to de-
`termine secondary treatment failure in many clinical studies. For example,
`the initial6-year data on sulfonylurea secondary failure rates among 1300
`diagnosed diabetics in the UKPDS relied on a fasting plasma glucose of
`greater than 270 mg/dL as the definition for treatment failure.2S
`As patients progress along the natural history of diabetes, multidrug
`combinations most likely are required to achieve glycemic goals. Pro-
`
`Page 8 of 19
`
`

`
`THE NATURAL HISTORY OF TYPE 2 DIABETES
`
`779
`
`0
`
`3
`6
`12
`9
`Time from Randomization
`
`(y)
`
`15
`
`A
`
`-~-u
`
`3
`
`6
`
`12
`9
`Time from Randomization
`
`15
`
`(y)
`
`<'-
`.c
`:t:
`o.-
`Q)~
`
`cr
`
`'C
`
`0
`
`B
`
`failure rates in the United Kingdom Prospective Diabetes Study
`Figure 4. Secondary
`(UKPDS). Fasting plasma glucose (FPG, A) and HbAlc (B) during the 11-year UKPDS. Sub-
`jects in the intensive treatment group (open circles), who were randomized to either insulin,
`metformin, or sulfonylurea, had an initial decrease in the FPG and HbAlc' Both conventional
`(solid circles) and intensive treatment groups, however, had similar rates of deterioration in
`glycemic control for the remainder of the study. (From 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; with permission.)
`
`,
`
`'
`
`I
`
`1: :, ~.
`:;;
`
`Ii
`I'
`j
`
`spective clinical trials with combination therapy are few in number; how-
`ever/ when monotherapy with sulfonylureas is inadequate, addition, not
`substitution, of another oral agent or exogenous insulin typically achieves
`improved control. For example, the combination of a sulfonylurea and
`metformin can be effective when patients are failing maximum doses of
`either medication used alone.3 In the US Pivotal trials, addition of met-
`
`Page 9 of 19
`
`

`
`780
`
`RAMLO-HALSTED & EDELMAN
`
`formin to the regimens of type 2 diabetics failing maximum doses of gly-
`buride led to a significant improvement in FPG levels. There was no ther-
`apeutic benefit, however, in replacing glyburide with metformin in these
`same subjects.4 Trials using troglitazone in combination with glyburide
`also have shown that this treatment strategy of adding, not substituting,
`for sulfonylureas can be extremely effective.6
`Very little information
`is available on the secondary failure rate of
`metformin. Early studies have reported a failure rate of 5% to 10% per
`year, similar to the failure rates of sulfonylureas. The UKPDS provided
`indirect evidence supporting these; earlier reports and suggested that the
`secondary failure rate for metformin would appear similar to what was
`seen with sulfonylureas (Fig. 4). The UKPDS data applicable to metformin
`as monotherapy, however, are difficult
`to determine because so few pa-
`tients remained on metformin alone for the duration of the study.
`Information is now becoming available on the secondary failure rate
`of the newest insulin sensitizer, troglitazone. This agent works mainly by
`improving peripheral insulin resistance in skeletal muscle and, to a lesser
`degree, by reducing excess hepatic glucose production. Troglitazone's ef-
`fect on the pancreatic ~-cell is still being studied, but clearly it does not
`directly stimulate insulin secretion. Given that troglitazone's primary af-
`fect is on insulin resistance, a pathogenic factor that is present throughout
`the continuum of IGT to mild type 2 diabetes to end-stage disease, it is
`anticipated that the secondary failure rate of this medication will be low
`relative to sulfonylurea therapy. It appears from several extension trials
`with troglitazone as mono therapy and in combination with sulfonylureas
`or insulin that the secondary failure rate for troglitazone is low.6 Figure 5
`demonstrates the secondary failure rate in the troglitazone/ sulfonylurea
`combination extension study (116 weeks); the subjects recruited for this
`study had diabetes for an average of 8 years before initial randomization.
`
`ROLE OF OBESITY IN INSULIN RESISTANCE
`AND TYPE 2 DIABETES
`
`Obesity has a profound impact on the progression of the diabetic state
`and on the patient's response to any particular
`form of treatment. For
`example, lean type 2 diabetics characteristically have a less severe insulin
`resistance and a more profound insulin secretory defect. These individuals
`typically respond better to exogenous insulin and medications that stim-
`ulate insulin secretion ("insulin secretagogues"). In contrast, obese dia-
`betics have a more profound degree of insulin resistance and compensa-
`tory hyperinsulinemia and tend to achieve better control with agents that
`improve insulin sensitivity such as biguanides (metformin) and thiazoli-
`dinediones (troglitazone).
`In the early 1980s, it became clear that central obesity often precedes
`the development of many metabolic disorders characterized by insulin
`resistance, including
`type 2 diabetes, hypertension, and cardiovascular
`disease. Central obesity is an increase primarily
`in visceral fat in the ab-
`
`Page 10 of 19
`
`

`
`THE NATURAL HISTORY OF TYPE 2 DIABETES
`
`781
`
`10.0
`
`9.5
`
`9.0
`
`7.5
`
`7.0
`
`6.5
`
`---~-~
`
`6.0 00\
`
`-4
`
`4
`
`12
`
`20
`
`28 36 44 52 60
`Weeks
`
`68
`
`76 84 92 100 108 116
`
`Figure 5. Troglitazone and sulfonylurea combination extension trial. Improvement in HbA,c
`with a combination of troglitazone (600 mg) and glynase (12 mg). Improvement in glycemic
`control obtained in the initial 52 weeks of therapy was sustained at 116 weeks. (From Draz-
`nin 8, Driscoll J, Sievers J, et al: Troglitazone plus sulfonylurea combination: Long-term ef-
`ficacy in patients with type 2 diabetes [abstract 0330]. In Diabetes: A Journal of the American
`Diabetes Association. American Diabetes Association, Chicago. 1998, p A8S; with permis-
`sion.)
`
`domen. Although this clinical association between insulin resistance and
`central obesity has been clear for some time, whether one condition causes
`the other or whether they develop concurrently still is controversial. It
`generally is agreed that the specific distribution of the increased adipose
`tissue, not just the presence of increased fat mass, is more important to
`the relationship between insulin resistance and obesity. A striking exam-
`ple of this point is a study comparing active and retired Japanese Sumo
`wrestlers.24 Sumo wrestlers still engaged in the sport have large amounts
`of subcutaneous abdominal
`fat and are quite insulin sensitive. Retired,
`inactive Sumo wrestlers and Japanese who have emigrated to the United
`States appear to redistribute
`their fat mass to visceral deposits, demon-
`strate clinically significant levels of insulin resistance, and have an in-
`creased incidence of type 2 diabetes and cardiovascular disease.
`
`RELATIVE PREVALENCE OF TYPE 2 DIABETES
`MELLITUS, IMPAIRED GLUCOSE TOLERANCE,
`AND INSULIN RESISTANCE: IMPLICATIONS
`FOR INTERVENTION
`
`The incidence of IGT and type 2 diabetes is rising annually because
`many of the major risk factors for these conditions are becoming more
`
`Page 11 of 19
`
`

`
`782
`
`RAMLO-HALSTED & EDELMAN
`
`prevalent (e.g., obesity, an increase in the mean age of the population,
`more sedentary lifestyles). Based on data from the National Health and
`Nutrition Examination Surveys (NHANES
`II and III), type 2 diabetes is
`on its way to becoming the most common chronic disease in the United
`States. An estimated 16 million Americans have type 2 diabetes, repre-
`senting more than 11 % of the population. Only half of those affected ac-
`tually are diagnosed and actively being treated. Approximately 600,000
`new cases of type 2 diabetes present each year in the United States. Al-
`though these numbers are staggering, the prevalence of IGT is estimated
`to be 22 million cases in the United States. Among American adults under
`74 years of age, 11% have IGT.16,17,27
`The prevalence of IGT and type 2 diabetes is just the tip of the iceberg
`when one considers the prevalence of the major pathogenic lesion itself:
`insulin resistance. Recall that insulin resistance is the featured defect in
`"syndrome X," a constellation of metabolic abnormalities
`that is even
`more common than type 2 diabetes and, like diabetes, is associated with
`an increased risk of cardiovascular disease. The prevalence of insulin re-
`sistance in the general population was the focus of a cross-sectional study,
`The Bruneck Study.2 Almost 900 subjects representing a cross-section of
`the general population, aged 40 to 79 years, were evaluated for the coex-
`istance of insulin resistance and one of a number of metabolic disorders.
`These disorders included IGT, type 2 diabetes, dyslipidemia, hyperuri-
`cemia, and hypertension. When the investigators considered the preva-
`lence of insulin resistance in each of the metabolic disorders separately,
`the prevalence of insulin resistance ranged from 58.0% (in subjects with
`hypertension)
`to 88.1 % (in subjects with lpw HDL). The prevalence of
`insulin resistance further increased to 95.2% when clusters of metabolic
`disorders were considered, such as the coexistance of IGT or diabetes with
`low HDL, hyperuricemia, and hypertension. In addition, individuals who
`were obese as defined by a BMI greater than 25 kg/ m2 and who had no
`other metabolic abnormalities had a prevalence of insulin resistance of
`42%. Clearly, insulin resistance is extremely prevalent and, given its path-
`ologic potential, may itself become a target for therapeutic intervention
`in the future.
`Significantly more clinical research attention is being paid to the non-
`obese, insulin resistant individual as someone who may benefit from early,
`preventative treatment. The term metabolically obese, normal weight individ-
`ual (MONW) has been coined to describe the person with hyperinsulin-
`emia, insulin resistance, and hypertriglyceridemia who is predisposed to
`premature coronary heart disease and type 2 diabetes.31 As the Brurteck
`study suggests, the MONW patient is probably quite commonly encoun-
`tered. Most likely, MONW represents one end of the spectrum of syn-
`drome X, just as IGT represents one end of the continuum
`leading to
`diabetes. Careful studies involving MONW subjects suggest that they
`have had small amounts of weight gain in adulthood; an increase of 4 to
`5 kg has been shown to be associated with clinically significant increases
`in the prevalence of diabetes and cardiovascular disease risk factors. Cer-
`tainly, these patients may benefit from diet, exercise, and perhaps phar-
`macologic intervention early in the course of their metabolic disease.
`
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`
`THE NATURAL HISTORY OF TYPE 2 DIABETES
`
`783
`
`MACROVASCULAR DISEASE AND IMPAIRED
`GLUCOSE TOLERANCE
`
`Current research efforts in the prevention of type 2 diabetes reflect a
`growing
`interest in also addressing the pathologic consequences of the
`prediabetic state, IGT. Few clinicians doubt that type 2 diabetics have a
`threefold increased risk of coronary artery disease, but too few clinicians
`realize that IGT is associated with at least a twofold increased risk. The
`NHANES
`II documented an increased prevalence of several cardiovas-
`cular findings in IGT subjects when compared with rates found in normal
`glucose tolerant individuals.16 Many of these findings-hypertension,
`an-
`gina, abnormal heart findings, and medical histories of arteriosclerosis
`and stroke-are
`signs or symptoms of macrovascular disease. As early as
`the 1970s, it has been clear that IGT is not itself associated with micro-
`vascular disease; the incidence of retinopathy and nephropathy correlate
`with the severity of hyperglycemia and duration of frank diabetes. In
`contrast, IGT is associated with an increased incidence of macrovascular
`disease and its complications. Impaired glucose tolerance and insulin re-
`sistance are associated with low levels of HDL cholesterol, increases in
`triglycerides, and hypertension. These metabolic problems in combination
`with changes in factors involved in the coagulation cascade may result in
`accelerated atherosclerosis and early macrovascular complications. In fact,
`prospective studies have since shown that cardiovascular risk factors are
`associated with a subsequent diagnosis of IGT, suggesting that there is
`overlap between the pathogenic mechanisms for macrovascular disease
`and IGT.26 Studies such as these underscore that.early intervention in pa-
`tients with IGT has the potential to delay progression to type 2 diabetes,
`but to treat early macrovascular disease actively.
`To underscore the association between insulin resistance and macro-
`vascular disease, many have proposed that syndrome X or the insulin re-
`sistance syndrome are not adequate terms. These phrases do not emphasize
`that cardiovascular disease and type 2 diabetes are clinically the most
`important complications of insulin resistance in terms of morbidity and
`mortality. A newly coined term cardiovascular dysmetabolic syndrome has
`been proposed.13,19.21 The diagnostic criteria are dyslipidemia,
`insulin re-
`sistance, obesity, and high blood pressure (DROP).~
`
`INTERVENTIONS TO ALTER THE NATURAL HISTORY
`OF TYPE 2 DIABETES
`
`As interest grows to investigate and promote clinical interventions to
`prevent the onset of type 2 diabetes and its vascular complications, some
`argue that IGT is not just a risk factor for type 2 diabetes but may also be
`a disease in itself, with associated complications of macrovascular disease.
`Impaired glucose tolerance, therefore, should be treated as a disease that
`is worthy of clinical screening and intervention.7 Furthermore, studies
`have shown that patients can move in and out of IGT. Between 30% to
`50% of patients with IGT who were followed
`for 2 to 17 years reverted
`
`IiI~
`
`Page 13 of 19
`
`

`
`784
`
`RAMLO-HALSTED & EDELMAN
`
`back to normal glucose tolerance.3o Therefore, there are potentially re-
`versible components of IGT that could be addressed before the progres-
`sion of I