Biology of Incretins: GLP-1 and GIP

The biology of incretin hormones.

Millions of years before we began to manipulate the flow of light using synthetic structures, biological systems were using nanometre-scale architectures to produce striking optical effects. An astonishing variety of natural photonic structures exists: a species of Brittlestar uses photonic elements composed of calcite to collect light, Morpho butterflies use multiple layers of cuticle and air to produce their striking blue colour and some insects use arrays of elements, known as nipple arrays, to reduce reflectivity in their compound eyes. Natural photonic structures are providing inspiration for technological applications.

Photonic structures in biology

GEFs and GAPs: Critical Elements in the Control of Small G Proteins

▪ Abstract Membrane fusion involves the merger of two phospholipid bilayers in an aqueous environment. In artificial lipid bilayers, fusion proceeds by means of defined transition states, including hourglass-shaped intermediates in which the proximal leaflets of the fusing membranes are merged whereas the distal leaflets are separate (fusion stalk), followed by the reversible opening of small aqueous fusion pores. Fusion of biological membranes requires the action of specific fusion proteins. Best understood are the viral fusion proteins that are responsible for merging the viral with the host cell membrane during infection. These proteins undergo spontaneous and dramatic conformational changes upon activation. In the case of the paradigmatic fusion proteins of the influenza virus and of the human immunodeficiency virus, an amphiphilic fusion peptide is inserted into the target membrane. The protein then reorients itself, thus forcing the fusing membranes together and inducing lipid mixing. Fusion of intr...

Membrane Fusion and Exocytosis

Although cAMP is well known to regulate exocytosis in many secretory cells, its direct target in the exocytotic machinery is not known. Here we show that cAMP-GEFII, a cAMP sensor, binds to Rim (Rab3-interacting molecule, Rab3 being a small G protein) and to a new isoform, Rim2, both of which are putative regulators of fusion of vesicles to the plasma membrane. We also show that cAMP-GEFII, through its interaction with Rim2, mediates cAMP-induced, Ca2+-dependent secretion that is not blocked by an inhibitor of cAMP-dependent protein kinase (PKA). Accordingly, cAMP-GEFII is a direct target of cAMP in regulated exocytosis and is responsible for cAMP-dependent, PKA-independent exocytosis.

cAMP-GEFII is a direct target of cAMP in regulated exocytosis.

Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion.

Voltage-dependent calcium (Ca2+) channels are involved in many specialized cellular functions1,2,3, and are controlled by intracellular signals such as heterotrimeric G-proteins4, protein kinases5,6 and calmodulin (CaM)7,8. However, the direct role of small G-proteins in the regulation of Ca2+ channels is unclear. We report here that the GTP-bound form of kir/Gem, identified originally as a Ras-related small G-protein that binds CaM9,10,11, inhibits high-voltage-activated Ca2+ channel activities by interacting directly with the β-subunit. The reduced channel activities are due to a decrease in α1-subunit expression at the plasma membrane. The binding of Ca2+/CaM to kir/Gem is required for this inhibitory effect by promoting the cytoplasmic localization of kir/Gem. Inhibition of L-type Ca2+ channels by kir/Gem prevents Ca2+-triggered exocytosis in hormone-secreting cells. We propose that the small G-protein kir/Gem, interacting with β-subunits, regulates Ca2+ channel expression at the cell surface.

Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem.

OBJECTIVE The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated. RESEARCH DESIGN AND METHODS The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell–conditioned media in the presence or absence of GLP-1 (7–37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated. RESULTS The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7–37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell–conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA 1c levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4. CONCLUSIONS Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.

https://diabetes.diabetesjournals.org/content/diabetes/60/9/2397.full.pdf

Beneficial Effects of Exendin-4 on Experimental Polyneuropathy in Diabetic Mice

Angiotensin II type 1 receptor blockers (ARBs) are widely used in the treatment of hypertension and have been shown to restore impaired intracellular insulin signaling and reduce the incidence of type 2 diabetes (1–3). Telmisartan has a unique property that activates peroxisome proliferator-activated receptor-γ (PPAR-γ) (4–6). We studied the effect of this unique property of telmisartan on insulin resistance and circulating levels of adiponectin and highly sensitive C-reactive protein (hs-CRP) in hypertensive patients with type 2 diabetes.

The study comprised 18 participants with hypertensive type 2 diabetes (9 men and 9 women) aged 36–79 years (64 ± 12, …

/pdf/replacement-of-valsartan-and-candesartan-by-telmisartan-in-4qt5jgpp4l.pdf

Nobuaki Ozaki

Papers

cAMP-GEFII is a direct target of cAMP in regulated exocytosis.

Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion.

Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem.

Beneficial Effects of Exendin-4 on Experimental Polyneuropathy in Diabetic Mice

Replacement of valsartan and candesartan by telmisartan in hypertensive patients with type 2 diabetes: metabolic and antiatherogenic consequences