Retrospective #99: “Natural History of Type 2 Diabetes”

“Natural History of Type 2 Diabetes” is a heading in a paper by Ralph A. DeFronzo, MD. Dr. DeFronzo is using the medical phrase “natural history” to describe the progression of a disease from incidence to diagnosis.

The paper was published in the American Diabetes Association’s magazine, Diabetes, after he presented the Banting award lecture at the ADA’s 2008 annual meeting in San Francisco. This paper caught my attention for a statement Dr. DeFronzo made about Pre-diabetes: “In summary, individuals with IGT [impaired glucose tolerance] are maximally or near-maximally insulin resistant, they have lost 80% of their β-cell function, and they have an approximate 10% incidence of diabetic retinopathy. By both pathophysiological and clinical standpoints, these pre-diabetic individuals with IGT should be considered to have Type 2 diabetes” (emphasis mine).

The takeaway from this is Dr. DeFronzo’s main point: We need a “new paradigm” of early intervention: “The clinical implications of these findings for the treatment of Type 2 diabetes are that the physician [my emphasis] must intervene early, at the stage of IGT [impaired glucose tolerance] or IFG [impaired fasting glucose].”

I am writing this blog primarily for patients in the hope that they will see the need to “intervene early” as well. It is so much easier to control your blood sugar if you have maximal insulin sensitivity and remaining beta cell function. 

DeFronzo begins, “Individuals destined to develop Type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin”  “In liver, the insulin resistance is manifested by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia and an impaired suppression of hepatic glucose production in response to insulin, as occurs following a meal.” (Translation: The liver overproduces glucose while we are fasting despite low blood insulin levels. That is why physicians now prescribe Metformin first to both suppress this unwanted glucose production -- called gluconeogenesis – and improve insulin sensitivity.)

“In muscle, the insulin resistance is manifest(ed) by impaired glucose uptake following ingestion of a carbohydrate meal and results in postprandial hyperglycemia.” “Both obesity and decreased physical activity are insulin resistant states and, when added to the genetic burden of insulin resistance, place a major stress on the pancreatic β-cells to augment their secretion of insulin to offset the defect in insulin action.” (Translation: insulin production increases to deal with both elevated levels of circulating glucose and our impaired insulin action due to insulin resistance.)

And here’s the crux of it: “As long as the β-cells are able to augment their secretion of insulin sufficiently to offset the insulin resistance, glucose tolerance remains normal.” (We have two faulty mechanisms at work here yet our blood glucose levels in response to both fed and fasting states are still NORMAL.) “However, with time the β-cells begin to fail and initially the postprandial plasma glucose levels and subsequently the fasting plasma glucose concentration begins to rise, leading to the onset of overt diabetes.” (Note: postprandial blood sugars rise first, then later fasting blood glucose.) That is the reason that the A1c test has replaced the fasting blood glucose test. The A1c test measures the average of all blood glucose values over a 3-month period and thus captures the elevated postprandial values in the average. Ask your doctor to do an A1c test. Medicare pays for 4 tests per year.)

“Collectively, the insulin resistance in muscle and liver and β-cell failure have been referred to as the triumvirate.” “The resultant hyperglycemia [elevated blood glucose] and poor metabolic control may cause further decline in insulin sensitivity, but it is the progressive β-cell failure that determines the rate of disease progression.”

Dr. DeFronzo’s paper then continues to describe his own research into the β-cell failure rate in detail but let this suffice: “Although the plasma insulin response to the development of insulin resistance typically is increased during the natural history of Type 2 diabetes, this does not mean that the β-cell is functioning normally. To the contrary, recent studies from our group have demonstrated that the onset of β-cell failure occurs much earlier and is more severe than previously appreciated.” That frightening statement is in plain English. I don’t think it requires any translation or interpretation on my part. We (doctors and patients) need a “new paradigm” of early intervention.