“Natural History of Type 2 Diabetes” is the heading of the first section of a scientific paper by Ralph A. DeFronzo, M. D. The full text can be found on the PubMed site here. It was also the basis of his Banting award lecture at the 2008 annual meeting of the American Diabetes Association in San Francisco. This paper caught my attention for the statement (cited in The Nutrition Debate #86 here) in which Dr. DeFronzo says in the section under Prediabetes, “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).
Dr. DeFronzo is using the medical phrase “natural history” to describe the progression of a disease from incidence to full-blown diagnosis. In this blog I will comment on quotes from this “history” section of Dr. DeFronzo’s paper to explain this progression and attempt to simplify the language to make it more user-friendly for the lay reader. I think his expert exposition of the stages of development of Type 2 diabetes is so important that it is worth the slog. Dr. DeFronzo’s point is that 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 must intervene early, at the stage of IGT [impaired glucose tolerance] or IFG [impaired fasting glucose].The main thrust of his presentation is that we need a “new paradigm” where “the physician must intervene early.” In writing this blog primarily for “patients” and other individuals who may have IGT or IFG, it is my hope that they will see the need to “intervene early” as well. It is much easier to control blood sugar if you have some 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.”(I don’t think the gene set is definitively known yet, but it surely will be soon.) “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.” (The liver overproduces glucose when we are in the fasting state despite low blood insulin levels. That is why physicians now usually prescribe Metformin first to both suppress this 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.” (Interesting. It’s the muscles.) “Although the origins of the insulin resistance can be traced to their genetic background, the epidemic of diabetes that has enveloped westernized countries is related to the epidemic of obesity and physical inactivity. 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.” (So, insulin production increases to deal with the combination of elevated levels of circulating glucose and our impaired insulin action due to insulin resistance.)
“As long as the β-cells are able to augment their secretion of insulin sufficiently to offset the insulin resistance, glucose tolerance remains normal.” (So, 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 that postprandial blood sugars rise first, then later fasting blood glucose.) That is the reason that the HbA1c test is rapidly replacing the fasting blood glucose test. The HbA1c test measures the average of all blood glucose values over a 3-month period and thus captures the elevated postprandial values in the average, whereas obviously the fasting blood glucose test does not. Ask your doctor to do an HbA1c test! An A1c over 5.5 indicates an increased risk for heart disease. In the U.S., if you have indications of Metabolic Syndrome, your insurance should pay for 4 tests per year.)
“Collectively, the insulin resistance in muscle and liver and β-cell failure have been referred to as the triumvirate. (This is again a reference to part of the title of Dr. DeFronzo’s presentation.) “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 pretty plain English. I don’t think it requires any interpretation on my part.