The Natural History of Progression From  Normal glucose Tolerance to Type 2 Diabetes in the Baltimore Longitudinal Study of Aging
Diabetes 52:1475-1484, 2003

1. Natural History of progression from
   
   
   • Normal glucose tolerance (NGT) to
   • Impaired Fasting Glucose (IFG) to
   • Impaired Glucose tolerance
   
   Is not well defined.
   
   
2. We concluded that phenotypic differences in rates of progression are partly a function of diagnostic thresholds, fasting and post challenge hyperglycemia may represent phenotypes with distinct natural histories in the evolution of type 2 diabetes.

Introduction

3. Type 2 diabetes is occurring in epidemic proportions worldwide


4. Type 2 diabetes can be prevented or delayed in subjects with impaired glycemia using:
• Behavior modifications
• Metformin
• Acarbose
• Troglitazone

Understanding the natural history is essential for early detection of prediabetic hyperglycemia and for interrupting the progression from normal to abnormal glucose tolerance.

1. IFG and IGT consistently predict increased risk for diabetes.
2. IGT is at least as strong a risk factor for diabetes as is IFG.
3. Isolated IGT with normal FPG is more common than isolated IFG.
4. 30-60 of subjects with IFT have normal FPG.
5. US recommendation is for FPG alone and assume that fasting hyperglycemia is an early abnormality in glucose tolerance common to:

• subjects with IFG
• those who will develop IGT
  
• All who develop type 2 diabetes

6. Abandonment of the OGTT may leave undetected a large proportion of subjects at risk for type 2 diabetes and the World Health Organization continues to support the use of OGGT.

Current data on the natural history of type 2 diabetes are derived primarily from prospective studies where a baseline OGTT has been followed after 1-11 years by a second OGTT.

1. Pima Indian data was from serial OGTTs
2. This data indicates a similar incidence rate of diabetes from FPG versus 2 hour PG.
3. Other studies showed higher levels of FPG and 2hPG predicted progression from IGT to diabetes.

Current data leave unanswered whether people:

• With normal glucose tolerance (NGT)
• Progress directly to diabetes or
• Develop diabetes only after a period of IFG or IGT or
• Whether people with IFG also eventually develop IGT or
• Vice versa people with IGT develop IFG

Before developing diabetes.

Metabolic data suggest there are differences between IFG and IGT in:

1. Insulin sensitivity
2. B-cell responsiveness
3. Hepatic glucose outpoint

Yet, it is unclear whether abnormal FPG or 2hPG represent a phenotype continuum or distinct phenotypic pathways to diabetes.

This study using OGTT collected from 3 to >10 biennial examination to determine whether abnormalities in fasting and postchallenge glycemia represent a continuum or distinct pathways in the natural history of type 2 diabetes.

Results

Progression from NGT to abnormal FPG and 2hPG

1. By 5 years,


• 31.1% had progressed to abnormal 2 hrPG
• 7.4% had progressed abnormal FPG


2. by 20 years


• 71.1% had progressed abnomal 2hrPG
• 38.7% had progressed to abnormal FPG


3. The annualized progression rate from NGT to abnormal 2hPG was about four time the rate of progression from NGT to abnormal FPG.


• Subjects older than 65 had substantially accelerated rates of progression to abnormal 2hPG compared to young subjects
• Subjects older than 65 had the same rates of progression to abnormal FPG as the younger subjects.


4. Men progressed to abnormal FPG or 2hPG more rapidly than women.


5. Subjects with overall or central obesity progressed to abnormal FPG or 2hrPG than lean subjects.


6. A family history of diabetes did not modify rates of progression to abnormal glucose tolerance.

Discussion

Differences in natural history of impairment of fasting versus postchallenge glycemia are in part a function of:

Diagnostic thresholds defining abnormal
But also suggest at least two distinct phenotypic pathways to diabetes.

1. More common is development of abnormal 2hPG levels with normal FPG.


• This pathway typically featured a prolonged decay in glucose tolerance, with slow progression form NGT to IGT to diabetic 2hrPG.
• Only a few cases on this pathway manifest IFG or diabetic FPG.


2. The less common and even slower pathway included development of IFG , or even more rarely development of diabetic FPG levels.


• However, virtually all of these subjects developed IGT or diabetic 1hPG
• Often an elevated 2hPG was the only abnormality diagnostic of type 2 diabetes.


3. These two phenotypes  abnormal 2hPG alone or abnormal FPG in combination with  2hPG  were apparent in the progression from both NGT to IFG and 2hPG and IGT to diabetes.


4. When the threshold for abnormal FPG was defines so that its prevalence approximated the prevalence of abnormal 2hPG, these differences virtually disappeared.


5. Rates of progression to IFG to diabetic FPG were indistinguishable from rates of progression to IGT or postchallenge diabetes.

In many cases the two pathways remained exclusive

1. About 42% of those who developed IFG did not develop IGT and vice versa.


2. Regardless of the threshold defining abnormal, serial OGTT revealed that at the population level, progression to type 2   diabetes unfolded over the course of decades.


3. Even after prolonged follow-up many subjects with IFG or IGT had not developed diabetes and many had reverted to NGT.


4. Standard risk factors for type 2 diabetes were:


• Older age
• Male sex
• Obesity.

Maintenance of normoglycemia results from:

1. A balance between glucose production


2. Glucose disposal mediated by skeletal muscle, pancreatic B-cells and the liver.

Insulin resistance and impaired first-phase insulin secretion are independent determinants of progression from NGT to IGT and from IGT to diabetes.

1. Comparing isolated IFG with isolated IGT suggest that variations in insulin resistance or insulin secretion may produce clinically distinct prediabetic phenotypes.


2. Pima Indians with IFG or IGT were equally insulin resistant


3. Pima Indians with IFG had a greater impairment of first-phase insulin secretion and higher basal hepatic endogenous glucose output compared with subjects with isolated IGT.


4. Pima Indians with IGT, only those with a relatively greater defect in first-phase insulin secretion subsequently developed type 2 diabetes.


5. Hepatic endogenous glucose output is a major determinant of FPG levels and in Pimas did not predict diabetes independent of insulin secretion and insulin resistance.


6. Similar results have been found in Caucasians.

Those with IFG and IGT had equivalent insulin resistance.
Those with IFG had depressed B-cell function, assessed using homeostasis model assessment (HOMA).