In order to study the heterogeneity of Type 2 (noninsulin-dependent) diabetes, we determined HLA antigens and measured B-cell function as C-peptide response to intravenous glucagon in 217 patients with onset of non-ketotic diabetes after the age of 40 years.
No clinical parameter was helpful to classify patients in one of these subclasses of diabetes; however, the glucagon-stimulated C-peptide was useful to discriminate between MODY2 patients and the others.
Its integrated action on carbohydrate metabolism results in reduction of circulating glucose, and GLP-1 has therefore been suggested as a therapeutic alternative in diabetes.
The therapeutic potential of glucagon-like peptide-1 (GLP-1) in improving glycaemic control in diabetes has been widely studied, but the potential beneficial effects of glucose-dependent insulinotropic polypeptide (GIP) have until recently been almost overlooked.
Three case subjects presented with neonatal diabetes that recurred at 4-17 years, while diabetes was incidentally discovered in the other case subject at 14 years of age. beta-Cell function was investigated after diabetes relapse by means of an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and glucagon tests.
A single administration of rAd-GLP-1 via the tail vein into streptozotocin (STZ)-induced diabetic non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice resulted in remission of diabetes within 10 days; normoglycemia remained until the experiment was terminated.
Patients with this diabetes subtype tested negative for islet autoantibodies, had a higher age of onset (median 28 vs 10 years, p < 0.001) and a markedly shorter duration from onset of hyperglycaemic symptoms to first hospital visit (median 3 vs 30 days, p < 0.001) than patients with non-fulminant type 1 diabetes, and showed trends of increased serum aspartate aminotransferase and amylase levels and a decreased glucagon-stimulated serum C-peptide response.
R164W segregated with diabetes in the family of the proband and in vitro studies showed that it impairs the repressor activity of PAX4 on the insulin and glucagon promoters.
Our study suggests that a DPP-IV inhibitor may prevent peripheral nerve degeneration in a diabetes-induced animal model and support the idea that GLP-1 may be useful in peripheral neuropathy.
These findings suggest that the GLP-1 pretreatment may be a new therapeutic strategy in the preventive and protective treatment during diabetes initiation and progression.
During the development of diabetes in P. obesus, a significant increase in GLP-1 was detected in the portal vein (9.8 ± 1.5 vs 4.3 ± 0.7 pmol/l, p < 0.05), and in pancreas extracts (11.4 ± 2.2 vs 5.1 ± 1.3 pmol/g tissue, p < 0.05).
In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration.
Peptide hormones of the glucagon-like peptide (GLP) family play an increasing clinical role, as reported for GLP-1 in diabetes therapy and insulinoma diagnostics.
Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02).
Although our observations with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.