Honjo International Scholarship Foundation
Doctoral Dissertation Presentation 2021
Presentation 8 by Oduori Sylvanus Okechi

Producing insufficient insulin yet diabetic? Your pancreatic beta-cells
have changed the major signaling pathway
Diabetes Mellitus, or simply diabetes, is a chronic disease that occurs either when thepancreas does not produce enough insulin or when the body cannot effectively use the insulin
it produces. Majorly classified as either type1(T1DM) or type 2 (T2DM), the latter accounts
for over 90% of all diabetes cases. Insulin is a hormone that regulates blood glucose. It isproduced by pancreatic beta (β) cells of the Islets of Langerhans. Glucose homeostasis isachieved by tight regulation of insulin secretion from pancreatic β cells in response to various
physiological factors, including nutrients and hormonal and neuronal inputs. Of these factors,
glucose is the primary initiator of insulin secretion. Glucose-induced insulin secretion (GIIS)
occurs through a sequence of precisely regulated events in pancreatic β cells. Transport ofglucose into β cells and enhanced glucose metabolism increase the ATP/ADP ratio, thereby
closing the ATP-sensitive K+ (KATP) channels. As KATP channel activity maintains a negative
resting membrane potential, closure of the channels causes membrane depolarization andactivates voltage-dependent Ca2+ channels (VDCCs), thereby leading to insulin release. TheKATP channels thus play a crucial role in linking the β cell’s metabolic status to its electricalactivity for the release of insulin. GIIS is amplified by hormones and neurotransmitters. Manyof these function by activation of the trimeric G proteins Gs and Gq. Among them, the incretins
glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP),
which are released by gut cells following meal ingestion, are critical for preventing
postprandial hyperglycemia by amplifying insulin secretion in a glucose concentration–
dependent manner. This is called “the incretin effect”. In non-diabetic subjects, the incretin
effect is responsible for 50-70% of insulin release during oral glucose administration, with GIP
contributing about 60% of the direct incretin effect on β cells. In type 2 diabetes patients,
although the incretin effect is impaired and contributes to only 20-35% of the insulin response
to oral glucose, the response to GIP is almost completely lost whereas that of GLP-1 is largely
preserved. Moreover, Asian T2DM patients, a majority in the world, exhibit retained incretineffect. Using this glucose-dependent effect, and the unique therapeutic potential of GLP-1,incretin-based drugs such as dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor
agonists (GLP-1RAs) have been developed and are increasingly used worldwide for diabetes
therapy. However, the reason why only GLP-1–based drugs are effective in improving insulin
secretion after presentation of diabetes has not been resolved. We generated β cell–specific
KATP knock out mice (βKcnj11–/– mice) to enable clarification of the direct role of the β cell KATP
channel in insulin secretion and glucose homeostasis. These mice exhibited severe glucose
intolerance and impaired GIIS, defects that can be corrected by GLP-1, but not by GIP,
indicating that the βKcnj11–/– mouse is a useful model for studying the mechanisms underlying
the differential effects of GLP-1 and GIP in insulin secretion in diabetes, as the model presentswith features remarkably similar to humans who develop T2DM. In addition to studying
βKcnj11–/– mice, we examined various in vivo and ex vivo models that mimic the inactive stateof KATP channels in β cells. We found that persistent depolarization induces a switch from Gs
to Gq signaling in β cells in these models and that similar changes are induced in human islets
by conditions emulating diabetes. We propose that this switch accounts for the clinicalobservation that GLP-1 but not GIP is effective in T2DM.