Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes

Abstract

Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATP-dependent potassium (K_ATP ) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage-gated potassium channels (K_v 7.1) and voltage-gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose-independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of K_ATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel-sensing mechanisms.

Keywords: beta cell; congenital hyperinsulinism; insulin secretion; monogenic diabetes.

Figure 1. Glucose-ramp stimulated insulin secretion in isolated islets

Rat, mouse and human islets were perifused with a glucose ramp (0 to 25 mM) stimulation with 0.625 mM/min increment. The threshold of glucose-stimulated insulin secretion is around 5 mM. N = 3 for each species, insulin was determined by homogeneous time resolved fluorescence assays. Data were adapted from Refs. , , , , .

Figure 2. Glucose metabolic pathways in beta cells

During glucose oxidation, different metabolic pathways are synchronized and integrated, ensuring that GSIS is tightly coupled with glucose oxidation. Glucose is first phosphorylated via glucokinase (GCK), then produce pyruvate through glycolysis. Pyruvate converts (1) to alanine via transamination (alanine aminotransferase, ALT); (2) to oxaloacetate (OAA) via pyruvate carboxylase (PC); (3) to Acetyl-CoA via pyruvate dehydrogenase (PDH). OAA and Acetyl-CoA enter tricarboxylic acid (TCA) cycle via citrate. Pyruvate cycling involves malate enzyme (ME) and PC. Aspartate switch represents the interexchange between OAA and aspartate via aspartate aminotransferase (AST). GABA shunt starts from glutamate decarboxylase (GAD) using glutamate as a substrate to produce GABA, GABA is then converted to succinate semialdehyde (SSA) via GABA transaminase (GABA-T) and subsequently to succinate via SSA dehydrogenase (SSADH). During glucose oxidation, phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GDH) are inhibited by high phosphate potential, leads to inhibition of glutaminolysis. In contrast, glucose stimulates glutamine synthesis via glutamine synthetase (GS).

Figure 3. Gene expression of ion channels in human beta cells

Based on RNA sequence data obtained from purified human beta cells, numbers of potassium channels (A), chloride channels (B), calcium channels (C), and sodium channels or transporters associate with sodium trafficking (D) are significantly expressed. Data were adapted from previously published RNA sequences.

Figure 4. Glucose “blindness” in SUR1 gene (Abcc8) knockout mice

The glucose-ramp stimulated insulin secretion in isolated and cultured islets from Abcc8 knockout and wild-type mice showed that Abcc8 knockout islets have higher basal insulin secretion but blinded to GSIS. Data were adapted from previously Ref. .

Figure 5. Glucose sensing in congenital hyperinsulinism or monogenic diabetes

Genetic disorders, including congenital hyperinsulinism (CHI), maturity-onset diabetes of the young (MODY) and permanent neonatal diabetes mellitus (PNDM), lead to abnormal glucose sensing in beta cell. Mutations in key steps of glucose oxidation or ion channels involve insulin secretion regulation result increased or decreased insulin secretion.

Figure 6. Amino acids-stimulated insulin secretion in mouse islets

Panel A shows insulin secretion from isolated and cultured wildtype mouse islets perifusions. Islets were perifused with a ramp of amino acid mixture (AAM) (0 to 12 mM) with (black circles) or without (gray triangles) 10 mM glucose pre-exposure. AAM ramp alone failed to stimulate insulin secretion, however, AAM potentiates glucose-stimulated insulin secretion. Panel B shows glucose independent AAM-stimulated insulin secretion in islets isolated from wild-type mice (blue), Hadh knockout mice (purple), Abcc8 knockout mice (red) and GDH transgenic mice (brown). Data were adapted from Refs. , , .

Figure 7. Amino acid sensing in congenital hyperinsulinism

Glucose-independent amino acid-stimulated insulin secretion or increased amino acid sensing in the beta cells lead to protein-induced hypoglycemia in 3 forms of congenital hyperinsulinism, including SCHAD deficiency, inactivating mutations of K_ATP channels and activating mutations of GDH.