Type 2 diabetes (
non-insulin-dependent diabetes mellitus,
NIDDM), at least in the majority of patients characterized by
insulin resistance and increased visceral fat, appears to be precipitated by the exposure of tissues to excessive levels of
free fatty acids; this can contribute to the muscle
insulin resistance, excessive hepatic gluconeogenesis, and beta cell dysfunction that collaborate to impair
glycemic control. The resultant
hyperglycemia, in turn, exacerbates the
insulin resistance and beta cells dysfunction. The failure of
glucose-stimulated insulin secretion (GSIS) in beta cells helps to sustain the elevations of serum
glucose and
free fatty acids, which in turn reinforce the failure of GSIS, possibly by inhibiting expression of the
transcription factor IDX-1;
NIDDM thus represents a vicious cycle that is not easily broken. A new strategy for achieving rapid loss of body fat - hepatothermic
therapy (HT), an integrated approach involving exercise training, low-fat, low-glycemic-index food choices, and a supplementation program that promotes hepatic
fatty acid oxidation - shows promise for alleviating the excessive fat exposure at the root of the diabetic syndrome, as well as the underlying
insulin resistance syndrome responsible for increased macrovascular risk. However, when HT proves incapable of breaking the vicious cycle sustaining beta cell dysfunction, a supplementary strategy, beta cell redifferentiation
therapy (BRT), may be required. BRT consists of a protocol in which near-normoglycemia is maintained for several weeks through use of intensive
insulin therapy (e.g.
artificial pancreas) or other effective measures, during which time beta cell GSIS can be expected to substantially recover owing to relief from glucolipotoxicity. Clinical experience demonstrates that this improved beta cell function, in certain cases, can persist for months or years after temporary BRT. A portion of the improved
glycemic control achieved with very
low calorie diets in
NIDDM is reflective of improved GSIS, presumably consequent to a sustained reduction in diurnal glycemia. Long-lived analogs of
glucagon-like peptide-1 (GLP-1) may find a key role in BRT; this
incretin hormone not only potentiates GSIS, but also appears to increase the expression and activity of IDX-1 in beta cells, thus promoting beta cell redifferentiation. If HT is instituted prior to and following BRT to alleviate the FFA overexposure that initially precipitated the diabetic syndrome, it seems likely that the benefits of BRT will be conserved in the long term, thus enabling a reversal of
NIDDM - in other words, maintenance of normoglycemia without medication. Since
NIDDM is inherently preventable, its reversal should be the fundamental goal of diabetes
therapy.