The pancreatic beta-cell recognition of insulin secretagogues. XII. Insulin release in response to halogenated hexosamines.
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Acetylgalactosamine↗
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Effects of insulin secretagogues on phospholipid metabolism in pancreatic beta-cells.
The effect of insulin secretagogues on the incorporation of [32-P] orthophosphate into phospholipids was studied in microdissected islets from obese-hyperglycemic mice. Increased 32-P-labelling was observed after incubation for 60 min with 10 mM L-leucine, 10 mM L-arginine or 20 mM D-glucose. Most of the label occurred in the phosphatidyl inositol fraction. The effect of L-leucine was additive to that induced by D-glucose while the effect of L-arginine was not. Glibenclamide (0.05 mM) was ineffective whether or not D-glucose was present. The results suggest that there is no direct correlation between the releasing actions of insulin secretagogues and changes in the metabolism of certain phospholipids and that phospholipid metabolism may be stimulated through more than one mechanism.
Animals↗
The mechanisms of action of chloromercuribenzene-p-sulphonic acid as insulin secretagogue: fluxes of calcium, sodium and rubidium in islets exposed to mercurial and a membrane-active antagonist.
Chloromercuribenzene-p-sulphonic acid (CMBS) is known to markedly stimulate insulin release and to enhance formation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and monovalent cation permeability in the pancreatic islet cells. The effects on insulin release and cyclic AMP can be inhibited with 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid (SITS). To elucidate the role of cationic fluxes in CMBS- induced insulin release, uptake of 22Na+ and 45Ca2+ as well as efflux of 86Rb+ were studied in islets exposed to 0-1 mM CMBS or 1-0 mM SITS or both. 2. The enhancing effect of CMBS on Na+ permeability, and probably also that on Rb+ permeability, was inhibited by SITS. 3. CMBS stimulated the rate of 45Ca2+ uptakes when the islets were incubated in a poly-anionic bicarbonate buffer but not when they were incubated in Tris buffer containing only Cl- as anion. In bicarbonate buffer, the enhancement of 45Ca2+ flux was observed both with the lanthanum method for measuring intracellular 45Ca2+ uptake and with a method estimating the total islet uptake. SITS had no significant effect on the CMBS-induced 45Ca2+ uptake. 4. Chromatography on Sephadex G-15 did not reveal any significant chemical interaction between 0-1 mM CMBS and 1 mM SITS. 5. The following hypothesis for the recognition of CMBS as insulin secretagogue is suggested: by increasing Na+ permeability more than K+ permeability, CMBS depolarizes the beta-cell, leading to initiation of insulin release by an ionic mechanism which may or may not involve a change in transmembrane Ca2+ fluxes. The marked intensity of the secretory response is due to the fact that CMBS also enhances cyclic AMP formation, potentiating the effect of the ionic mechanisms on the insulin discharge apparatus.
4-Chloromercuribenzenesulfonate↗
Insulin release and the microtubular system of the islets of Langerhans: effects of insulin secretagogues on microtubule subunit pool size.
An assay system was devised to estimate the pool size of microtubule subunits in islet cells, and to study the importance of the equilibrium between polymerised microtubules and their subunits in the regulation of insulin release. The assay was based on the observation that colchicine binds specifically and quantitatively to microtubule protein subunits, but not to intact microtubules. Vinblastine and cold treatment, which have been shown to cause disaggregation of microtubules into subunits and to inhibit insulin release from islets, increased the number of colchicine binding subunits. D2O, which promotoes stability of microtubules and increases their number in islet cells, caused a decrease in subunit concentration. These results suggest that changes in the equilibrium between polymerised microtubules and their subunits could be studied by measuring the size of the subunit pool. When insulin release was stimulated, by incubating islets in high glucose concentrations or by increasing the intracellular concentration of cyclic AMP there was a reduction in the content of subunit protein. Conversely, when insulin release was inhibited by removal of calcium from the incubation medium there was a shift in the microtubule subunit equilibrium to give an increase in the number of subunits assayed. These results indicate that changes in the equilibrium between subunits and microtubules may play an important role in regulating rates of insulin secretion.
Animals↗
Alloxan-induced alteration of insulin release, rubidium efflux and glucose metabolism in rat islets stimulated by various secretagogues.
Insulin release and 86Rb efflux were studied in perifused rat islets exposed in vitro to alloxan (2 mmol/l) for 5 min. At a low glucose concentration, alloxan transiently increased 86Rb efflux. Alloxan immediately and completely abolished the secretory response to glucose (15 mmol/l) and markedly delayed the reduction in 86Rb efflux normally produced by the sugar. 3-O-methylglucose (20 mmol/l) provided complete protection against the alteration of 86Rb efflux and partial protection against the inhibition of insulin release. Immediately after alloxan treatment, glyceraldehyde, alpha-ketoisocaproic acid and tolbutamide still induced a rapid release of insulin, but the late phase normally stimulated by glyceraldehyde and alpha-ketoisocaproic acid was inhibited. If islets were exposed to glyceraldehyde or tolbutamide 15 min after alloxan treatment, the rapid insulin release was also markedly impaired. Alloxan failed, however, to affect the ability of these three stimuli to reduce 86Rb efflux from islet cells. Glucose oxidation and utilization were decreased in alloxan-treated islets and 3-O-methylglucose protected against this effect. The results show that the glucose recognition system in B-cells is the most rapidly and severely affected by alloxan. The drug also alters the response to other secretagogues, the insulin releasing properties of which can be impaired without alteration of their ability to reduce 86Rb efflux.
Alloxan↗
Serum and pancreatic immunoreactive insulin (IRI) and proinsulin-like component (PLC), serum IRI and PLC response to different stimuli in normal subjects and organic hyperinsulinism.
The serum levels of total immunoreactive insulin (IRI) and proinsulin-like component (PLC) in the fasting state and following the administration of insulin secretagogues in 5 patients with organic hyperinsulinism and age and sex matched normal subjects are reported. Diagnosis of organic hyperinsulinism could be established in all instances on the basis of the inappropriately high total serum IRI levels for the corresponding blood glucose values; such an abnormal relationship was not seen in normal subjects, and was further enhanced by insulin secretagogues. Unrestrained insulin secretion in organic hyperinsulinism was enhanced following the administration of glucose, tolbutamide, glucagon or amino acids; the last 2 stimuli are known to be ineffective in causing insulin secretion in the presence of hypoglycemia in normal subjects. Four patints had insulinomas and one probably had islet cell hyperplasia or abnormal function of islet cells. Chromatography of serum IRI to quantitate PLC is a useful adjunct to the diagnosis of organic hyperinsulinism as in the fasting state the proportion of PLC is always elevated, above the normal range of 5-22%. Following the administration of insulin secretagogues there was pronounced increase in total serum IRI in organic hyperinsulinism but the proportion of PLC generally decreased, suggesting thereby that mojor increase in IRI was due to release of stored granular IRI which is known to have a low proportion of PLC.
Adenoma, Islet Cell↗
Accumulation of dopamine in mouse pancreatic B-cells following injection of L-DOPA. Localization to secretory granules and inhibition of insulin secretion.
Accumulation and subcellular localization of dopamine (DA) in pancreatic B-cells and its effects on insulin secretion were investigated in mice following a single injection of L-3,4-dihydroxyphenylalanine (L-DOPA). Electron microscopic autoradiography showed that 3H-DA formed from administered 3H-DOPA was present over B-cells as well as over other types of islet cells. Pretreatment of the animals with a decarboxylase inhibitor greatly reduced the number of autoradiographic grains. In the B-cells the 3H-DA-grains were associated with the secretory granules. The location of the label may suggest an incorporation in the periphery of the beta-granule, rather than in the dense core, supposed to contain insulin. Accumulation of DA in the B-cells following L-DOPA administration was found to inhibit partially the insulin secretory response to different insulin secretagogues (glucose, glibenclamide and L-isopropylnoradrenaline (L-IPNA). Treatment with monoamine oxidase inhibitor + L-DOPA induced an almost total suppression of L-IPNA-stimulated insulin secretion, whereas glucose-induced insulin release was still only partially inhibited. Pretreatment with a decarboxylase inhibitor abolished the effects of L-DOPA. It is suggested that intracellularly accumulated DA in the B-cell exerts an inhibitory action on insulin releasing mechanisms induced by different secretagogues and that this action might involve interference with a calcium translocation process at the level of the secretory granule.
Animals↗
Modifying actions of calcium ionophores on insulin release.
Beta-Cell-rich pancreatic islets were microdissected from noninbred ob/obmice and exposed to the calcium ionophores X-537A and A-23187. X-537A differed from A-23187 in being a potent insulin secretagogue at non-stimulating glucose concentrations. Both ionophores inhibited the stimulation of insulin release obtained after adding 20 mM glucose to the incubation medium. The latter observation is consistent with the idea of a reduced beta-cell function when the Ca-2+ in the functionally important intracellular pool (s) exceeds a certain concentration. The ionophore inhibition of the glucose-stimulated insulin release may at least in part result from decreased formation of cyclic AMP, since X-537A proved to be as effective as L-epinephrine in reducing the islet content of this nucleotide in the presence of a phosphodiesterase inhibitor. The secretagogic action of X-537A at a low glucose concentration persisted when different ions were omitted from the incubation medium and was actually considerably enhanced in the absence of extracellular Ca-2+. The insulin-releasing action of X-537A was neither influenced by 3-O-methyglucose nor by drugs blocking the alpha or beta-adrenergic receptor sites. Exposure of the pancreatic beta-cells to metabolic inhibitors in concentrations which significantly reduced the secretory response to glucose, potentiated stimulation of insulin release by X-537A, suggesting that this effect may in part be accounted for by intracellular dissolution of secretory granules.
Animals↗
Carbohydrate content and regulation following injection of different glycogenolytic enzymes.
The effect of injection of glycogenolytic enzymes on tissue glycogen, blood glucose and plasma insulin was studied in mice. No effects were observed following phosphorylase, whereas the hydrolytic enzymes, alpha-amylase and acid amyloglucosidase depressed liver glycogen. In addition acid amyloglucosidase induced a decrease in blood glucose, a slight elevation of plasma insulin and a marked increase in tolbutamide-stimulated insulin release. At the doses given none of the enzymes affected muscle glycogen. Amyloglucosidase pretreatment markedly enhanced insulin release induced by glibenclamide, leucine, isoleucine, lysine and glucose whereas insulin release stimulated by IPNA, ACTH, glucagon and "CCK-PZ" was unaffected. Injection of acid amyloglucosidase has a profound influence on carbohydrate content and regulation in mice. It is suggested that the dependence or independence of amyloglucosidase activity among the insulin secretagogues tested might reflect different or partially different mechanisms in the process of insulin secretion.
Adrenocorticotropic Hormone↗
Effects of various modifiers of insulin release on the lanthanum-nondisplaceable 45Ca2+ uptake by isolated pancreatic islets.
The uptake of 45Ca2+ by a lanthanum-non-displaceable pool in pancreatic islets was studied; Raising the extracellular D-glucose concentration from 3 to 20 mM stimulated the 45Ca2+ uptake in hand-dissected islets of ob/bo-mice as well as in collagenase-isolated islets of ob/ob or normal mice. The effect was dose-dependent in the range of 0-20 mM D-glucose and was seen throughout a wide range of extracellular calcium concentrations (16 mumol-2.56 mmol of Ca2+ added per litre of medium). The 45Ca2+ uptake was also enhanced by other known insulin secretagogues (D-mannose, L-leucine, tolbutamide) and was uninfluenced by compounds lacking insulin-releasing capacity (3-O-methyl-D-glucose, L-glucose, D-galactose, D-leucine). The stimulatory effect of D-glucose was blocked by inhibitors of glucose-induced insulin release (D-mannoheptulose, diazoxide, L-adrenaline). The results support the view that the lanthanum-nondisplaceable calcium pool is related to the insulin-releasing mechanism, although the exact nature of this relationship is still unclear.
Animals↗
Studies on the function of pancreatic islet cell membranes.
Pancreatic islets rich in beta-cells were isolated from non-inbred ob/ob-mice and used for studying various aspects of the function of the plasma membrane. A review is given of the authors' work along the following lines: the role of transmembrane transport or membrane binding in the recognition of insulin-releasing sugars, amino acids, sulfonylureas, and sulphydryl-blocking agents; the role of cyclic 3',5'-AMP and cations in the coupling of stimulus recognition to insulin discharge; alloxan beta-cytotoxicity in vitro and its prevention by sugars; the isolation of a subcellular fraction enriched by plasma membranes. 1. It is suggested that D-glucose is recognized as an insulin secretagogue by being metabolized in the beta-cells; the teleological purpose of the transmembrane transport system being to allow fluctuations of the extracellular glucose concentration to be rapidly transmitted to the cell interior. Insulin-releasing sulfonyluraes and sulphydryl reagents are thought to act directly on the beta-cell plasma membrane, however. 2. Although cyclic 3',5'-AMP may amplify the expression of a secretory signal induced by D-glucose, studies with cholera toxin suggest that activation of the adenylate cyclase does not per se elicit secretion. The increase of islet cyclic 3',5'-AMP observed in response to several secretagogues, including D-glucose, may be secondary to membrane depolarization. 3. The possible role of an electrodiffusional mechanism in controlling the electrical potential is emphasized; a decrease of K+ permeability, rather than an increase of Na+ permeability, is suggested to be involved in the depolarizing action of D-glucose. Studies with the lanthanum-wash technique indicated that D-glucose causes a net flux of Ca2+ from the outside to the inside of the beta-cells. Although this uptake may relate to the enhancement of insulin secretion, the detailed mechanisms are unclear. 4. Inhibition of the Na+/K+ pump may be one of the earliest events in damage to the beta-cell by alloxan, on the basis of Rb+ studies. Protective effects of glucose against alloxan toxicity appear to be close related. 5. Studies of enzyme markers, the binding of wheat germ agglutinin, and electron microscopy indicate the presence of plasma membranes in a smooth-membrane fraction obtained by fractionating islet homogenates at consecutive sucrose gradients.
Alloxan↗
Studies on the role of beta-cell metabolism in the insulinotropic effect of alpha-ketoisocaproic acid.
alpha-Ketoisocaproic acid has been shown to be a potent insulin secretagogue but the mechanism has not been elucidated. To define the role of beta-cell metabolism in the insulinotropic activity of alpha-ketoisocaproic acid the utilization of glucose and the oxidation of alpha-ketoisocaproic and isovaleric acid by incubated islets of obese hyperglycemic mice were measured. Glucose metabolism was never enhanced by alpha-ketoisocaproic acid. The same 14CO2 amounts were released from the non-secretagogue [1-14C]isovaleric acid (10 mM) or from alpha-keto[2-14C]isocaproic acid (5--20 mM). Pyruvate (20 mM) did not inhibit alpha-ketoisocaproic acid-induced insulin secretion in spite of reduction of decarboxylation of alpha-ketoisocaproic acid by more than 40%. The results indicate that stimulated insulin release in response to alpha-ketoisocaproic acid is not mediated by an indirect increase in glucose metabolism and further suggest that isovaleryl-CoA and following CoA-esters in alpha-ketoisocaproic acid degradation are not likely recognized as signals. The possibility, however, remains that enhanced intramitochondrial production of reducing equivalents elicits insulin secretion.
Animals↗
Effect of vinblastine in vivo on ultrastructure and insulin releasing capacity of the B-cell following sulphonylurea and isopropyl-noradrenaline.
The effect of vinblastine in vivo on ultrastructure and insulin releasing capacity of the B-cell was studied in mice. Treatment with vinblastine (1.1 mumole/mouse) resulted in a 75% decrease of the amount of normal microtubules and the appearance of characteristic paracrystals. Basal plasma immunoreactive insulin levels were depressed to about 60% of the control level. The dose-response pattern for insulin release (first phase) following two chemically unrelated insulin secretagogues, the potent sulphonyl-urea derivative, glibenclamide, and the beta-adrenegic agonist L-isopropylnoradrenaline, (L-IPNA), was tested with and without vinblastine pretreatment. The dose-response curves for L-IPNA-induced insulin release in vinblastine-treated and control animals did not deviate significantly from each other, whereas insulin release following glibenclamide was almost totally suppressed by vinblastine except at the lowest dose level. Injection of maximal doses of glibenclamide or L-IPNA did not alter the ultrastructural changes induced by vinblastine in the B-cells. It is suggested that the microtubular system of the B-cell might play a minor role for certain insulin-releasing processes and/or that vinblastine might have other important effects on the insulin secretory machinery.
Animals↗
Pancreatic beta cell replication: effects of hexose sugars.
Neonatal rat pancreatic monolayer cultures were utilized to investigate the effects of various hexose sugars on insulin release and beta cell replication. Sugars tested were D-glucose, L-glucose, 3-O-methyl-D-glucose, D-mannose and D-fructose. These agents were added at varying concentrations to a control medium containing a baseline level of 5.5 mM D-glucose. Replication was estimated by incubating cultures with [3H]thymidine and determining the frequency of beta cell labelling in aldehyde-thionin stained radioautographs. Although the addition of D-glucose to the control medium resulted in a concentration-dependent increase in both insulin release and beta cell replication, the sensitivity of these two processes to glucose differed. Insulin release was stimulated by a 2.75 mM elevation in the D-glucose concentration of the control medium, while an elevation of 11 mM D-glucose was required to increase the frequency of beta cell replication. Moreover, while insulin release was maximally stimulated by an 11 mM elevation in the concentration of D-glucose, the frequency of replication continued to rise as the concentration of D-glucose was further increased. The specificity of these responses to D-glucose was demonstrated by the inability of 11 mM L-glucose or 11 mM 3-O-methyl-D-glucose to stimulate beta cell replication. D-mannose and D-fructose were less potent insulin secretagogues than D-glucose on an equimolar basis and neither compound enhanced beta cell replication at a concentration of 11 mM. However, higher concentrations of D-mannose (16.5 and 22 mM) enhanced beta cell replication, while comparable concentrations of D-fructose did not. These results indicate that the sensitivity of insulin release and beta cell replication to D-glucose differ, and that in addition to D-glucose, D-mannose is also capable of stimulating beta cell replication.
Animals↗
Further studies on the metabolism of D-glucose anomers in pancreatic islets.
The alpha and beta anomers of commercially available D-(5-3H) glucose were separated by miniaturized Hudson-Dale procedures based on precipitation with acetic acid. Reflectometric measurements of the reactivity with matrix-bound glucose oxidase showed that the preparations were about 90 per cent pure with respect to anomeric composition. Nonradioactive anomers separated by the same procedures were analyzed by optic polarimetry and gas chromatography. The preparations were about 90 per cent pure with respect to anomeric composition and produced no peaks but D-glucose on trimethylsilylation and chromatography. Microdissected pancreatic islets of noninbred ob/ob-mice exhibited a linear production of 3H2O for three to nine minutes when incubated with 6 mM alpha-D-(5-3H) glucose, beta-D-(5-3H) glucose, or D-(5-3H) glucose in anomeric equilibrium; the three glucose preparations did not differ in their rate of conversion to 3H2O. The rate of 3H2O production increased with glucose concentration (3-21 mM) during incubations for three minutes and, again, there was no evidence for the metabolic activity's being dependent on the anomeric composition of the labeled sugar. When microdissected islets were perifused without glucose and suddenly exposed to 5-6 mM alpha-D-glucose or beta-D-glucose, the concentration of glucose-6-phosphate rose within five minutes and did not differ significantly between experiments with alpha-D-glucose and beta-D-glucose. In the same perifusion experiments, only alpha-D-glucose caused a pronounced stimulation of insulin secretion, the difference from beta-D-glucose being significant. The results indicate that the recognition of glucose as an insulin secretagogue does not only involve metabolism by glucose-6-phosphate. The possible roles of the sorbitol pathway and of hypothetical regulatory sites for the glucose molecule ("receptors") are briefly discussed.
Animals↗
Calcium distribution in islets of Langerhans: a study of calcium concentrations and of calcium accumulation in B cell organelles.
Calcium concentrations of various pancreatic B cell organelles have been determined by X-ray microanalysis of areas of frozen sections of unfixed rat islets of Langerhans. Highest concentrations were detected in storage granules and in mitochondria, although calcium was also present in nuclei, in areas of endoplasmic reticulum and of cytoplasm. Accumulation of 45Ca by isolated organelles has been studied in homogenates and isolated subcellular fractions of rat islets of Langerhans. In the presence of a permeant anion (oxalate or phosphate), accumulation of 45Ca into mitochondria and microsomes was strongly stimulated by ATP. This net uptake was diminished during incubation of homogenates or of a mitochondria plus storage granule-rich fraction in the presence of cyclic AMP, dibutyryl cyclic GMP; 2:4-dinitrophenol or of ruthenium red. Investigations of the characteristics of 45Ca accumulation by homogenates prepared from storage granule-depleted islets showed no differences from those of normal islets, suggesting that the granules do not represent an important labile pool of calcium. With the exception of cyclic AMP and cyclic GMP none of the insulin secretagogues tested (glucose, leucine, arginine, adrenalin, noradrenalin, theophylline, glibenclamide) altered calcium accumulation by islet homogenates. On the basis of absolute calcium levels and of 45Ca uptake studies it is concluded that islet B cells contain a readily exchangeable mitochondrial calcium pool, and an endoplasmic reticulum pool containing a lower concentration of calcium which is also readily exchangeable. The storage granules, despite their high calcium content, do not appear to constitute a labile pool. It seems likely that the labile mitochondria and endoplasmic reticulum pools play a predominant role in the regulation of cytoplasmic free calcium levels, which may in turn be important in the regulation of rates of insulin secretion.
Adenosine Monophosphate↗
Proinsulin and C-peptide: a review.
The recent work on proinsulin and C-peptide has been reviewed with major emphasis on the most significant findings since 1972. Proinsulin has now been established as the biosynthetic precursor of insulin in all species examined, including man, with a preproinsulin as a possible precursor of the prohormone. The conversion of proinsulin which appears to occur exclusively in the pancreas leads to equimolar production of insulin and C-peptide. Although proinsulin has a direct biologic effect which is one-tenth as much as that of insulin, C-peptide has no biologic activity on homologous or heterologous tissue and no ability to modify the action of insulin and/or proinsulin. Previous work on proinsulin immunoassay suggested that this prohormone, but not C-peptide, cross-reacts with insulin antiserum. On the other hand, in the C-peptide immunoassay, proinsulin but not insulin cross-reacts with the antiserum. Up to this time, therefore, it has not been possible to immunoassay human proinsulin or C-peptide specifically. The very recent work from the laboratory of Heding, however, has brought about major advances in this area in which human C-peptide and proinsulin can be separated in the plasma by the use of Sepharose particles. With this recent major advancement, it is now possible to measure human C-peptide specifically. This measurement has been shown to be a useful tool for the assessment of beta-cell function in diabetic patients treated with insulin and in insulinoma patients in whom endogenous C-peptide secretion is not suppressed with exogenous insulin-induced hypoglycemia. With the use of a specific enzyme which degrades insulin but not proinsulin, postprandial plasma proinsulin values have been measured in a large number of subjects under a variety of physiologic and pathologic conditions. These results, which are comparable to those obtained by the more laborious column chromatography, could be summarized as follows: (1) proinsulin values in lean, young normal subjects do not vary greatly in response to insulin secretagogues; (2) proinsulin secretion in response to glucose results in a greater percentage of proinsulin in the older age group than in the younger group; (3) in lean adult and juvenile diabetic patients, the percentage of proinsulin is not excessive, whereas obese diabetics and pregnant diabetics appear to secrete relatively greater proinsulin than their diabetic controls; and (4) whereas most hyperinsulinemic states (Cusing's syndrome, adult-onset diabetics, acromegaly, and glucocorticoid therapy) are not associated with an increase in percentage of proinsulin, hyperinsulinemia of insulinoma, selected cases of functional hypoglycemia, and genetic hyperproinsulinemia are associated with a greater percentage of proinsulin. Identification of a possible new proinsulin intermediate(s) in these conditions deserves further investigation...
Amino Acid Sequence↗
Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.
Sulfonylureas are a cornerstone of type 2 diabetes therapy despite interindividual variability in response. Despite well-documented sex-based differences, pharmacogenomic and genome-wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex-stratified GWAS of hemoglobin A1c (HbA1c) response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (N = 871). Variants meeting genome-wide (P < 5.0 × 10-8) and suggestive (P < 5.0 × 10-6) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10, and SPINK5 (combined-sex); CRACR2A, KCNK2, and TENM2 (male-only); and NACPH2 (female-only). Two suggestive variants in the TMEM64/NECAB1 locus, associated with reduced HbA1c response to sulfonylureas in the male-only ACCORD analysis, were directly replicated in the PMET1 male-only cohort. In SUGAR-MGH, one replicated variant (rs6471250-C) was significantly associated with reduced peak insulin in males (P = 0.035) but not females (P = 0.40), demonstrating sex-specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation/sensitivity, calcium signaling, potassium-channel biology, and glucose transport. The findings highlight sex-specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex-specific precision medicine. Identification of genetic variants influencing sex-specific response could inform dosing to optimize sulfonylureas.
Humans↗