Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Skeletal muscle insulin resistance may be aggravated by intramyocellular accumulation of fatty acid-derived metabolites that inhibit insulin signaling. We tested the hypothesis that enhanced fatty acid oxidation in myocytes should protect against fatty acid-induced insulin resistance by limiting lipid accumulation. L6 myotubes were transduced with adenoviruses encoding carnitine palmitoyltransferase I (CPT I) isoforms or -galactosidase (control). Two to 3-fold overexpression of L-CPT I, the endogenous isoform in L6 cells, proportionally increased oxidation of the long-chain fatty acids palmitate and oleate and increased insulin stimulation of [ Insulin resistance in skeletal muscle is frequently present in obesity and is an early characteristic of the development of type 2 diabetes mellitus. Consistent with the association between insulin resistance and obesity, multiple lines of inquiry suggest a close relationship between the development of disease and disordered lipid metabolism. In particular, in both rodent (1, 2) and human (3-6) studies, a correlation has been observed between the degree of insulin resistance in vivo and the triacylglycerol content of muscle cells, the primary target for insulin-stimulated glucose disposal. A possible causal relationship has been proposed in which the high plasma fatty acid levels frequently observed in the obese/insulin-resistant state drive muscle lipid accumulation that in turn causes a predisposition toward decreased insulin sensitivity and worsening of the disease, the so-called "lipotoxic" model of skeletal muscle insulin resistance. Evidence for this hypothesis comes from a series of in vivo model systems in which artificial elevations in plasma fatty acid levels over several hours induced lipid build-up and insulin resistance in muscle tissue (7-10). Parallel observations have been made in vitro in which incubation of model muscle cells in tissue culture with fatty acids has analogous consequences (11-13).Although the association between increased intramyocellular lipid and the development of insulin resistance is compelling, the mechanism of the effect is far from clear. For example, triacylglycerol accumulation in muscle cells is not invariably associated with insulin resistance. Notably the muscle of trained endurance athletes has been shown to be highly insulin-sensitive despite the presence of high levels of intramyocellular triacylglycerol (14), and shorter term (4-week) exercise training in humans appears to improve muscle insulin sensitivity in the absence of measurable changes in muscle triacylglycerol content (15). To account for this apparent discrepancy, it has been proposed that triglyceride accumulation within insulin-resistant muscle is merely a marker for some other harmful fatty acid-derived metabolite(s). In particular, diacylglycerol (16), ceramide (17), and long-chain acyl-CoA (18) are also elevated in certain insulin-resistant muscle models. Each of these has been implicated in mediating the negative effects of lipids on insulin signaling via ...
Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues. That IL-6 may be responsible in great measure for these increases in AMPK is suggested by the fact it increases AMPK activity both in muscle and adipose tissue in vivo and in incubated muscles and cultured adipocytes. In addition, we have found that AMPK activity is diminished in muscle and adipose tissue of 3-month-old IL-6 knockout (KO) mice at rest and that the absolute increases in AMPK activity in these tissues caused by exercise is diminished compared with control mice. Except for an impaired ability to exercise and to oxidize fatty acids, the IL-6 KO mouse appears normal at 3 months of age. On the other hand, by age 9 months, it manifests many of the abnormalities of the metabolic syndrome including obesity, dyslipidemia, and impaired glucose tolerance. This, plus the association of decreased AMPK activity with similar abnormalities in a number of other rodents, suggests that a decrease in AMPK activity may be a causal factor. Whether increases in IL-6, by virtue of their effects on AMPK, contribute to the reported ability of exercise to diminish the prevalence of type 2 diabetes, coronary heart disease, and other disorders associated with the metabolic syndrome remains to be determined. Diabetes 55 (Suppl. 2):S48 -S54, 2006
GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue, and pancreas. We have recently shown that young GPR39(-/-) mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type and GPR39(-/-) mice as they aged from 12 to 52 wk or when fed a low-fat/high-sucrose or high-fat/high-sucrose diet. Fifty-two-week-old GPR39(-/-) mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a low-fat/high-sucrose or high-fat/high-sucrose diet, GPR39(-/-) mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from wild-type and GPR39(-/-) mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 beta-cells revealed that GPR39 regulates the expression of insulin receptor substrate-2 and pancreatic and duodenal homeobox-1 in a cell-autonomous manner; insulin receptor substrate-2 mRNA was also significantly decreased in the pancreas of GPR39(-/-) mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. on development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes.
Glucagon-like peptide 1 (GLP-1) is the most potent physiological incretin for insulin secretion from the pancreatic -cell, but its mechanism of action has not been established. It interacts with specific cell-surface receptors, generates cAMP, and thereby activates protein kinase A (PKA). Many changes in pancreatic -cell function have been attributed to PKA activation, but the contribution of each one to the secretory response is unknown. We show here for the first time that GLP-1 rapidly released free fatty acids (FFAs) from cellular stores, thereby lowering intracellular pH (pH i ) and stimulating FFA oxidation in clonal -cells (HIT). Similar changes were observed with forskolin, suggesting that stimulation of lipolysis was a function of PKA activation in -cells. G lucagon-like peptide 1 (GLP-1) is the most potent potentiator of glucose-induced insulin secretion that has been described (1,2). This peptide causes the elevation of cAMP and the activation of protein kinase A (PKA) (3); however, it releases insulin only in the presence of stimulatory glucose (4) and thus serves as an incretin rather than a secretagogue (5). Activation of PKA leads to phosphorylation of multiple -cell proteins, many of which have been hypothesized to play a role in insulin secretion (6-8). The nature of the endogenous substrates for PKA that may potentiate insulin secretion is unknown. Because the islet contains large stores of triglycerides (9), particularly in diabetes (10), another possible role of the normal rise in cAMP could be to stimulate lipolysis (via lipase activation), thereby providing the cell with free fatty acids (FFAs). Recent research on hormone-sensitive lipase (HSL) in -cells yielded results consistent with that notion (11). The released FFAs may directly effect secretion, or they may do so indirectly via generation of other lipids, including the putative long-chain acyl CoA (LC-CoA) signal, diacylglycerol (DAG), and phosphatidic acid (PA) (12). The acute addition of exogenous FFAs is also known to enhance glucose-stimulated secretion (9,13-15).We have shown in previous studies that added FFAs cause acidification in -cells (16) and fat cells (17) as a consequence of the flip-flop mechanism of diffusion across the plasma membrane (16,17). Furthermore, we have shown in adipocytes that the elevation of cAMP stimulates lipolysis, with a resulting decrease in the intracellular pH (pH i ) caused by the release of FFAs, which become partially ionized (17). Therefore, in this study we assessed whether GLP-1 has a similar effect on lipolysis in -cells. Our data show a decrease in pH i and a release of FFAs by agents that increase cAMP, presumably via activation of HSL. Furthermore, the incretin effect was largely diminished by a lipase inhibitor, whereas glucose-stimulated secretion was less affected. These findings indicate that cAMP-mediated lipolysis may play an important role in -cell signal transduction and the incretin effect of GLP-1. RESEARCH DESIGN AND METHODSGrowth and incubation of cells. Clonal pancr...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.