Berberine in the Treatment of Diabetes Mellitus: A Review.

Berberine is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and hypolipidemic activities. The research proves that it also strongly impacts carbohydrate metabolism. The compound also protects pancreatic ß-cells and increases sensitivity to insulin in peripheral tissues via the induction of GLUT-1, GLUT-4 and insulin type 1 (Ins-1) receptors activity. It also stimulates glycolysis and leads to a decrease in insulin resistance by macrophages polarization, lipolytic processes induction and energy expenditure enhancement (by reducing body mass and limiting insulin resistance caused by obesity). In liver berberine inhibits FOX01, SREBP1 and ChREBP pathways, and HNF-4α (hepatocyte nuclear factor 4 alpha) mRNA that hinder gluconeogenesis processes. In the intestines it blocks α-glucosidase contributing to glucose absorption decrease. Its interference in intestinal flora reduces levels of monosaccharides and suppresses diabetes mellitus complications development.

The Powdered Root of Eurycoma longifolia Jack Improves Beta-Cell Number and Pancreatic Islet Performance through PDX1 Induction and Shows Antihyperglycemic Activity in db/db Mice.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder worldwide. In addition to the chief feature of long-standing hyperglycemia, dyslipidemia, hyperinsulinemia, and a number of complications develop in parallel. It is believed that an adequate control of blood glucose levels can cause these complications to go into remission. This study was performed to evaluate the antidiabetic activity of Eurycoma longifolia Jack (EL) in vivo. The blood-glucose-lowering activity of EL was studied in db/db mice administered crude powdered EL root (25, 50, and 100 mg/kg) orally for eight weeks. At the end of the study, HbA1c, insulin, plasma lipid levels, and histopathology were performed. Powdered EL root showed significant antihyperglycemic activity along with the control of body weight. After eight weeks of treatment, both the blood cholesterol level and the glycogen deposit in hepatocytes were remarkably lower, whereas the secreting insulin level was elevated. An improvement in islet performance was manifested as an increase in beta-cell number and pancreatic and duodenal homeobox 1 (PDX1) expression. Neogenesis or formation of new islets from pancreatic duct epithelial cells seen in the EL-treated group was encouraging. This study confirms the antihyperglycemic activity of EL through PDX1-associated beta-cell expansion resulting in an enhancement of islet performance.

Diazoxide Preconditioning of Nonhuman Primate Pancreas Improves Islet Isolation Outcomes by Mitochondrial Protection.

OBJECTIVES: Previously, we showed that diazoxide (DZ), an effective ischemic preconditioning agent, protected rodent pancreas against ischemia-reperfusion injury. Here, we further investigate whether DZ supplementation to University of Wisconsin (UW) solution during pancreas procurement and islet isolation has similar cytoprotection in a preclinical nonhuman primate model. METHODS: Cynomolgus monkey pancreata were flushed with UW or UW + 150 µM DZ during procurement and preserved for 8 hours before islet isolation. RESULTS: First, a significantly higher islet yield was observed in UW + DZ than in UW (57,887 vs 23,574 IEq/pancreas and 5396 vs 1646 IEq/g). Second, the DZ treated islets had significantly lower apoptotic cells per islet (1.64% vs 9.85%). Third, DZ significantly inhibited ROS surge during reperfusion with a dose-response manner. Fourth, DZ improved in vitro function of isolated islets determined by mitochondrial potentials and calcium influx in responses to glucose and KCI. Fifth, the DZ treated islets had much higher cure rate and better glycemia control in diabetic mice transplant model. CONCLUSIONS: This study showed a strong mitochondrial protection of DZ on nonhuman primate islets against ischemia-reperfusion injury that provides strong evidence for its clinical application in islet and pancreas transplantation.

Necrostatin-1 supplementation enhances young porcine islet maturation and in vitro function.

BACKGROUND: Necroptosis has been demonstrated to be a primary mechanism of islet cell death. This study evaluated whether the supplementation of necrostatin-1 (Nec-1), a potent inhibitor of necroptosis, to islet culture media could improve the recovery, maturation, and function of pre-weaned porcine islets (PPIs). METHODS: PPIs were isolated from pre-weaned Yorkshire piglets (8-15 days old) and either cultured in control islet culture media (n = 6) or supplemented with Nec-1 (100 µM, n = 5). On days 3 and 7 of culture, islets were assessed for recovery, insulin content, viability, cellular composition, GLUT2 expression in beta cells, differentiation of pancreatic endocrine progenitor cells, function, and oxygen consumption rate. RESULTS: Nec-1 supplementation induced a 2-fold increase in the insulin content of PPIs on day 7 of culture. When compared to untreated islets, Nec-1 treatment doubled the beta- and alpha-cell composition and accelerated the development of delta cells. Additionally, beta cells of Nec-1-treated islets had a significant upregulation in GLUT2 expression. The enhanced development of major endocrine cells and GLUT2 expression after Nec-1 treatment subsequently led to a significant increase in the amount of insulin secreted in response to in vitro glucose challenge. Islet recovery, viability, and oxygen consumption rate were unaffected by Nec-1. CONCLUSION: This study underlines the importance of necroptosis in islet cell death after isolation and demonstrates the novel effects of Nec-1 to increase islet insulin content, enhance pancreatic endocrine cell development, facilitate GLUT2 upregulation in beta cells, and augment insulin secretion. Nec-1 supplementation to culture media significantly improves islet quality prior to xenotransplantation.

Protective effects of either C-peptide or l-arginine on pancreatic ß-cell function, proliferation, and oxidative stress in streptozotocin-induced diabetic rats.

Diabetes and cardiometabolic risk factors including hypertension and dyslipidemia are the major threats to human health in the 21st century. Apoptosis in pancreatic tissue is one of the major causes of diabetes type 1 progression. The aim of this study was to investigate the effects of C-peptide or l-arginine on some cardiometabolic risk factors, pancreatic morphology, function and apoptosis, and the mechanisms of their actions. Forty adult male albino rats were divided into four equal groups: 1-control nondiabetic, 2-diabetic (no treatment), 3-diabetic + C-peptide, and 4-diabetic + l-arginine. Diabetes was induced by a single intraperitoneal injection of high dose streptozotocin. At the end of the experiment, sera glucose, insulin levels, total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NO), and pancreatic MDA, TAC, and B-cell lymphoma 2 were measured. The morphology and proliferating activity of the pancreas were examined by hematoxylin and eosin histological stain, proliferative cell nuclear antigen (PCNA), and insulin antibodies. Our results showed that induction of diabetes caused hyperglycemia, dyslipidemia, and oxidative stress. However, administration of C-peptide or l-arginine significantly improved the pancreatic histopathology with a significant increase in the area % of insulin immunoreactivity, the number of PCNA immunopositive cells, the number of islets, and the diameter of islets compared with the diabetic group. C-peptide treatment of the diabetic rats completely corrected these errors, while l-arginine partially antagonized the above diabetic complications. So the administration of C-peptide as an adjuvant therapy in type 1 diabetes can significantly decrease apoptosis of pancreas and subsequent progression of diabetes complication.

Resveratrol Influences Pancreatic Islets by Opposing Effects on Electrical Activity and Insulin Release.

SCOPE: Resveratrol is suggested to improve glycemic control by activation of sirtuin 1 (SIRT1) and has already been tested clinically. Our investigation characterizes the targets of resveratrol in pancreatic beta cells and their contribution to short- and long-term effects on insulin secretion. METHODS AND RESULTS: Islets or beta cells are isolated from C57BL/6N mice. Electrophysiology is performed with microelectrode arrays and patch-clamp technique, insulin secretion and content are determined by radioimmunoassay, cAMP is measured by enzyme-linked immunosorbent assay, and cytosolic Ca2+ concentration by fluorescence methods. Resveratrol (25 µmol L-1 ) elevates [Ca2+ ]c and potentiates glucose-stimulated insulin secretion. These effects are associated with increased intracellular cAMP and are sensitive to the SIRT1 blocker Ex-527. Inhibition of EPAC1 by CE3F4 also abolishes the stimulatory effect of resveratrol. The underlying mechanism does not involve membrane depolarization as resveratrol even reduces electrical activity despite blocking KATP channels. Importantly, after prolonged exposure to resveratrol (14 days), the beneficial influence of the polyphenol on insulin release is lost. CONCLUSION: Resveratrol addresses multiple targets in pancreatic islets. Potentiation of insulin secretion is mediated by SIRT1-dependent activation of cAMP/EPAC1. Considering resveratrol as therapeutic supplement for patients with type 2 diabetes mellitus, the inhibitory influence on electrical excitability attenuates positive effects.

Improvement of isolated caprine islet survival and functionality in vitro by enhancing of PDX1 gene expression.

BACKGROUND: Dead islets replaced with viable islets are a promising offer to restore normal insulin production to a person with diabetes. The main reason for establishing a new islet source for transplantation is the insufficiency of human donor pancreas while using xenogeneic islets perhaps assists this problem. The expression of PDX1 is essential for the pancreas expansion. In mature ß-cells, PDX1 has several critical roles such as glucose sensing, insulin synthesis, and insulin secretion. In this study, we aimed to evaluate the expression of pancreatic duodenal homeobox-1 (PDX1) in treated caprine islets in culture and to assess the protective effects of antioxidant factors on the PDX1 gene in cultured caprine islets. MATERIALS AND METHODS: Purified islets were treated with serum-free, serum, IBMX, tocopherol, or IBMX and tocopherol media. Quantitative polymerase chain reaction and Western blotting were carried out to compare the expression levels of PDX1 in treated purified islets cultured with different media. RESULTS: Islets treated with IBMX/tocopherol exhibited the highest fold change in the relative expression of PDX1 on day 5 post-treatment (relative expression: 6.80±2.08), whereas serum-treated islets showed the lowest fold changes in PDX1 expression on day 5 post-treatment (0.67±0.36), as compared with the expression on day 1 post-treatment. Insulin production and viability tests of purified islets showed superiority of islet at supplemented serum-free media with IBMX/tocopherol compared to other cultures (53.875%±1.59%). CONCLUSIONS: Our results indicated that supplemented serum-free medium with tocopherol and IBMX enhances viability and PDX1 gene expression compared to serum-added and serum-free media.

Red Ginseng Administration Before Islet Isolation Attenuates Apoptosis and Improves Islet Function and Transplant Outcome in a Syngeneic Mouse Marginal Islet Mass Model.

BACKGROUND: Transplantation of isolated islets is a promising treatment for diabetes. Red ginseng (RG) is steamed ginseng and has been reported to enhance insulin secretion-stimulating and anti-apoptotic activities in pancreatic ß-cells. In this study, we examined the hypothesis that pre-operative RG treatment enhances islet cell function and anti-apoptosis and investigated whether RG improves islet engraftment by transplant of a marginal mass of syngeneic islets pretreated with RG in diabetic mice. METHODS: Balb/c mice were randomly divided into 2 groups, and 1 group was administered RG (400 mg/kg/day orally) for 7 days before islet isolation. In vitro islet viability and function were assessed. After cytokine treatment, cell viability, function, and apoptosis of islet cells were analyzed. Furthermore, we studied the effects of RG in a syngeneic islet graft model. A marginal mass of syngeneic mouse islets was transplanted into diabetic hosts. RESULTS: Islet pretreatment with RG showed 1.4-fold higher glucose-induced insulin secretion than did control islets. RG pretreatment upregulated B-cell lymphoma 2 (Bcl-2) expression and downregulated Bcl-associated X protein (BAX), caspase-3, and inducible nitric oxide synthase (iNOS) expression. Glucose-induced insulin release, NO, and apoptosis were significantly improved in RG-pretreated islets compared with cytokine-treated islets. RG-pretreated mice exhibited improved marginal mass islet graft survival compared with controls. CONCLUSIONS: These results suggest that pre-operative RG administration enhanced islet function before transplantation and attenuated cytokine-induced damage associated with apoptosis. These studies indicate that inhibition of apoptosis by RG significantly improved islet cell and graft function after isolation and transplantation, respectively.

Antihyperlipidemic and biochemical activities of Mcy protein in streptozotocin induced diabetic rats.

BACKGROUND: This study was aimed to evaluate the protective effects of a novel anti-hyperglycemic "Mcy protein" isolated from the fruits of Momordica cymbalaria in streptozotocin induced- diabetes rat model. MATERIALS AND METHODS: Wild type and Streptozotocin induced diabetic male wistar albino rats were either treated with single intraperitoneal injection of 2.5 mg Mcy protein/kg body weight or acetate buffer daily for 30 days. Fasting blood glucose and, serum and tissue lipid levels were measured along with biochemical analysis for hepatic and renal function tests. RESULTS: Mcy protein significantly reduced the fasting blood glucose and, serum as well as tissue lipid levels (p<0.05), besides normalizing the levels of liver and kidney function markers in the treated diabetic rats when compared to the diabetic controls. Our studies also showed the pancreatic islet regeneration in Mcy treated rats. CONCLUSION: Mcy protein can alleviate hyperlipidemia and help manage diabetes by stimulating insulin secretion without evident toxic effects on liver and kidney.

High Recovery of Functional Islets Stored at Low and Ultralow Temperatures.

BACKGROUND: Poor recovery of islets upon cryopreservation is the main hurdle in islet banking. Pancreatic islets have a poor antioxidative defense mechanism, and exposure of islets to low temperature leads to oxidative stress. AIM: We aimed to investigate whether known compounds such as metformin, γ aminobutyric acid (GABA), docosahexanoic acid (DHA), or eicosapentaenoic acid (EPA) alone or in combination are capable of reducing oxidative stress for better islet recovery upon storage at suboptimal temperatures. METHODS: Islets isolated from mouse pancreas were stored at low temperature (4°C) for 15 days and at ultralow temperature (-196°C) for 30 days with or without additives. After revival from cold storage, islets were assessed by using three methods: (1) specificity by dithizone (DTZ), (2) viability by fluorescein diacetate/propidium iodide (FDA/PI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) assay, and (3) functionality by glucose-stimulated insulin secretion (GSIS). The oxidative status of the islets stored at suboptimal temperatures was determined by both intracellular free radical release (fluorometric analysis) and lipid peroxidation (enzymatic determination). RESULTS: Supplementation with additives led to an improvement in islet survival upon storage at suboptimal temperatures, without depletion of insulin secretory activity, which was comparable to that of controls. The additives acted as cryoprotectants and antioxidants as revealed by high recovery of viable islets and reduction in total reactive oxygen species (ROS) and malonidealdehyde (MDA), respectively. CONCLUSIONS: Our results demonstrate for the first time that supplementation with EPA, DHA, and metformin may lead to higher islet recovery from -196°C storage, enabling proper islet banking.

Development of in vitro 3D TissueFlex® islet model for diabetic drug efficacy testing.

Increasing individuals diagnosed with type II diabetes pose a strong demand for the development of more effective anti-diabetic drugs. However, expensive, ethically controversial animal-based screening for anti-diabetic compounds is not always predictive of the human response. The use of in vitro cell-based models in research presents obviously ethical and cost advantages over in vivo models. This study was to develop an in vitro three-dimensional (3D) perfused culture model of islets (Islet TF) for maintaining viability and functionality longer for diabetic drug efficacy tests. Briefly fresh isolated rat islets were encapsulated in ultrapure alginate and the encapsulated islets were cultured in TissueFlex(®), a multiple, parallel perfused microbioreactor system for 7 days. The encapsulated islets cultured statically in cell culture plates (3D static) and islets cultured in suspension (2D) were used as the comparisons. In this study we demonstrate for the first time that Islet TF model can maintain the in vitro islet viability, and more importantly, the elevated functionality in terms of insulin release and dynamic responses over a 7-day culture period. The Islet TF displays a high sensitivity in responding to drugs and drug dosages over conventional 2D and 3D static models. Actual drug administration in clinics could be simulated using the developed Islet TF model, and the patterns of insulin release response to the tested drugs were in agreement with the data obtained in vivo. Islet TF could be a more predictive in vitro model for routine short- and long-term anti-diabetic drug efficacy testing.

The effects of oral carvacrol treatment against H2O2 induced injury on isolated pancreas islet cells of rats.

Pancreatic islet transplantation is an alternative treatment of insulin replacement therapy in diabetes mellitus, but the islets are exposed to many chemical, mechanical damages, and oxidative stress before transplantation. Carvacrol is a well-known essential oil for its antioxidant, antimicrobial, antifungal and antiinflammatory properties. The aim of this study was to investigate the possible protective effects of carvacrol against H 2O 2 induced cellular injury on isolated pancreas islets. After carvacrol (20, 40 and 80 mg/kg/day) treatment, the pancreas islets were isolated by enzyme digestion. The isolated islets were incubated within 0, 150 and 300 µM H 2O 2 containing medium at +4°C for 15 min. Then, the islets were examined with fluorescein diacetate and propidium iodide mixture stains for viability. A number of islets were stored for lipid peroxidation, protein oxidation and DNA fragmentation analysis. The cell viability ratio of Carvacrol 20 mg/kg/day group was increased in comparison to control and vehicle (DMSO) groups. Additionally, carvacrol application protected the cells from lipid peroxidation and protein oxidation induced by H 2O 2. H 2O 2 caused tissue injury and DNA fragmentation. There was only one DNA fragmentation band from islet cells of 20 mg/kg/day carvacrol treated group, however there were more than one bands from control and DMSO groups. In conclusion, carvacrol treatment ameliorates islet cell injury induced by H 2O 2. However, the dose of carvacrol is important and our results suggest that 20 mg/kg/day dose is more effective than doses of 40 or 80 mg/kg/day.

High-fat diets containing soybean or canola oil affect differently pancreas function of young male rats.

The excessive fat intake generally might induce obesity and metabolic disturbances. Thus, the goal of the study was to assess the role of high-fat diets containing soybean or canola oil on intra-abdominal adiposity and pancreatic morphology and function of young rats. After weaning, rats were fed with a control diet (7S) or a high-fat diet containing soybean oil (19S) or canola oil (19C) until they were 60 days old, when they were sacrificed. Food intake (g/day), body mass and length, retroperitoneal and epididymal fat mass, HOMA-IR, HOMA-ß and area of pancreatic islets were assessed. The results were considered different with a significant level of p<0.05. Both 19S and 19C groups showed higher body mass, length, and retroperitoneal fat mass. The 19C group showed higher HOMA-IR (+43% and +78%) and HOMA-ß (+40% and +59%) than 19S and 7S groups, respectively. Both 19S and 19C groups showed lower pancreatic islets area in relation to 7S group. Meantime, 19C presented lower percentage of pancreatic islets area in comparison to 19S (-41%) and 7S group (-70%, p<0.0001). Independent of soybean or canola oil, the high fat diet promoted development of the obesity. Comparing 19C and 19S groups, the higher concentrations of monounsaturated fatty acids, present in the canola oil were worse than higher concentrations of polyunsaturated fatty acids, present in the soybean oil.

4-Deoxypyridoxine improves the viability of isolated pancreatic islets ex vivo.

The successful islet transplantation, for the treatment of type 1 diabetes, depends on the quantity and the quality of transplanted islets. Previously, it has reported that the significant loss of isolated islet mass could be prevented by sphingolipid metabolite, sphinogosine 1-phophate (S1P). This study was performed to elucidate whether the beneficial effects of S1P maintaining isolated pancreatic islets ex vivo are mimicked by modulation of intracellular S1P. We tested the in vitro effect of various agents that modulate intracellular S1P levels in insulinoma cell lines and isolated islets to compare their anti-apoptotic effects with that of S1P. As results, we discovered that 4-deoxypyridoxine (DOP), which inhibits the degradation of intracellular S1P by inhibiting S1P lyase (SPL) activity, minimized the chemically induced apoptosis of insulinoma cell lines as S1P did. Also, supplementation of DOP in the culture media protected the regression of isolated islets that have been maintained ex vivo at least for 18 h providing the evidence of increasing viability of isolated islets with DOP, which impaired SPL activity. In conclusion, these results suggest that the application of SPL inhibitors could be considered as a supplement for the maintenance of viable islets isolated from donor sources in the process of islet transplantation.

Brain control of insulin and glucagon secretion.

Islet hormones, especially insulin and glucagon, are important for glucose homeostasis. Insulin is a necessity for life, and disturbed insulin release results in disordered blood glucose regulation. Although isolated islets are fully capable of detecting changes in their local environment (particularly glucose fluctuations) and altering hormone release appropriately, experimentally manipulating pancreatic innervation alters islet hormone release in the whole animal. This article describes how brain may play a role in influencing and directing secretion of insulin and glucagon as a key part of the integrated physiology of blood glucose homeostasis.

Chronic exposure to leucine in vitro induces ß-cell dysfunction in INS-1E cells and mouse islets.

Chronic hyperglycemia and hyperlipidemia cause deleterious effects on ß-cell function. Interestingly, increased circulating amino acid (AA) levels are also a characteristic of the prediabetic and diabetic state. The chronic effects of AAs on ß-cell function remain to be determined. Isolated mouse islets and INS-1E cells were incubated with or without excess leucine. After 72 h, leucine increased basal insulin secretion and impaired glucose-stimulated insulin secretion in both mouse islets and INS-1E cells, corroborating the existence of aminoacidotoxicity-induced ß-cell dysfunction. This took place concomitantly with alterations in proteins and genes involved in insulin granule transport, trafficking (e.g. collapsin response mediator protein 2 and GTP-binding nuclear protein Ran), insulin signal transduction (proteasome subunit α type 6), and the oxidative phosphorylation pathway (cytochrome c oxidase). Leucine downregulated insulin 1 gene expression but upregulated pancreas duodenum homeobox 1 and insulin 2 mRNA expressions. Importantly, cholesterol (CH) accumulated in INS-1E cells concomitantly with upregulation of enzymes involved in CH biosynthesis (e.g. 3-hydroxy-3-methylglutaryl-CoA reductase, mevalonate (diphospho) decarboxylase, and squalene epoxidase) and LDL receptor, whereas triglyceride content was decreased. Our findings indicate that chronic exposure to elevated levels of leucine may have detrimental effects on both ß-cell function and insulin sensitivity. Aminoacidotoxicity may play a pathogenic role in the development of type 2 diabetes.

Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice.

Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated ß-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.

Regulation and functional effects of ZNT8 in human pancreatic islets.

Zinc ions are essential for the formation of insulin crystals in pancreatic ß cells, thereby contributing to packaging efficiency of stored insulin. Zinc fluxes are regulated through the SLC30A (zinc transporter, ZNT) family. Here, we investigated the effect of metabolic stress associated with the prediabetic state (zinc depletion, glucotoxicity, and lipotoxicity) on ZNT expression and human pancreatic islet function. Both zinc depletion and lipotoxicity (but not glucotoxicity) downregulated ZNT8 (SLC30A8) expression and altered the glucose-stimulated insulin secretion index (GSIS). ZNT8 overexpression in human islets protected them from the decrease in GSIS induced by tetrakis-(2-pyridylmethyl) ethylenediamine and palmitate but not from cell death. In addition, zinc supplementation decreased palmitate-induced human islet cell death without restoring GSIS. Altogether, we showed that ZNT8 expression responds to variation in zinc and lipid levels in human ß cells, with repercussions on insulin secretion. Prospects for increasing ZNT8 expression and/or activity may prove beneficial in type 2 diabetes in humans.