Abstract
Type 2 diabetes mellitus (T2DM) is characterized by a progressive failure of pancreatic β-cell function (BCF) with insulin resistance. Once insulin over-secretion can no longer compensate for the degree of insulin resistance, hyperglycemia becomes clinically significant and deterioration of residual β-cell reserve accelerates. This pathophysiology has important therapeutic implications. Ideally, therapy should address the underlying pathology and should be started early along the spectrum of decreasing glucose tolerance in order to prevent or slow β-cell failure and reverse insulin resistance. The development of an optimal treatment strategy for each patient requires accurate diagnostic tools for evaluating the underlying state of glucose tolerance. This review focuses on the most widely used methods for measuring BCF within the context of insulin resistance and includes examples of their use in prediabetes and T2DM, with an emphasis on the most recent therapeutic options (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists). Methods of BCF measurement include the homeostasis model assessment (HOMA); oral glucose tolerance tests, intravenous glucose tolerance tests (IVGTT), and meal tolerance tests; and the hyperglycemic clamp procedure. To provide a meaningful evaluation of BCF, it is necessary to interpret all observations within the context of insulin resistance. Therefore, this review also discusses methods utilized to quantitate insulin-dependent glucose metabolism, such as the IVGTT and the euglycemic-hyperinsulinemic clamp procedures. In addition, an example is presented of a mathematical modeling approach that can use data from BCF measurements to develop a better understanding of BCF behavior and the overall status of glucose tolerance.
Highlights
Antihyperglycemic Therapy MET None SFU METdiet and exercise (D/E), MET, SFU, or MET+SFU None NoneSFU MET±SFU or Glinide NoneGLIB up to BL None during study hemoglobin A1c (HbA1c), %bFasting Glucose, mmol/Lb not given (NG) not applicable (NA)Body Weight, kgb 102.0c 100.3c NG NG
homeostasis model assessment (HOMA) was first introduced during the seminal United Kingdom Prospective Diabetes Study (UKPDS) where it was used to track the long-term effectiveness of various treatments frequently used in the 1980s, with follow-up of a large population of patients with Type 2 diabetes mellitus (T2DM) [4,5,6]
Any perceived improvements in -cell function (BCF) while patients are in treatment are not sustained upon discontinuation of the drugs. These effects may be apparently lost immediately after discontinuation of the GLP-1 RECEPTOR AGONIST (GLP-1RA) therapy, there seems to be a long-term imprint effect on the first-phase insulin secretion, which is worth pursuing in all patients with T2DM who can tolerate, and are good candidates for, GLP-1RA therapy. Improvements in both homeostatic and dynamic measures of BCF have been consistently demonstrated across the GLP-1RA drug class, but whether these have any impact on the natural history of the disease, which translates into clinical benefits to patients with T2DM, remains to be determined
Summary
-cell dysfunction with progressive loss of pancreatic cell insulin secretion, subsequent to the development of insulin resistance, are key defects associated with the transition from a healthy glycemic state to hyperglycemia, characteristic of untreated type 2 diabetes mellitus (T2DM) (Fig. 1) [1, 2]. Prior to overt T2DM (prediabetes), individuals with normal glucose tolerance (NGT) develop progressive insulin. As a part of this, there is overproduction of endogenous glucose in the basal state, despite the presence of fasting hyperinsulinemia, and impaired suppression of postprandial glucose (PPG) production, both of which are markers of insulin resistance. Patients with overt T2DM have either HbA1c 6.5% or an FPG 7.0 mmol/L or a 2-hour post-OGTT or random plasma glucose value 11.1 mmol/L. Evidence suggests that therapy should be started early along the spectrum of decreasing glucose tolerance to prevent progression of the disease with its complications, avoid complete -cell failure, and reverse insulin resistance. Ating the benefits of early diagnosis and the effectiveness of various treatments for prediabetes and T2DM are presented, with an emphasis on the most recent therapeutic options
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