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PubMed1997

A genetic selection for isolating cDNAs encoding secreted proteins.

We describe a simple, rapid technique for simultaneously isolating large numbers of cDNAs encoding secreted proteins. The technique makes use of a facile genetic selection performed in a strain of Saccharomyces cerevisiae deleted for its endogenous invertase gene. A cDNA cloning vector which carries a modified invertase gene lacking its leader sequence is used in conjunction with this strain. Heterologous secreted genes fused appropriately upstream of this defective invertase provide the necessary signals to restore secretion, allowing the yeast to grow on sugars such as sucrose or raffinose. This microbial growth selection facilitates scanning cDNA libraries containing millions of clones, enabling the wholesale identification of novel secreted proteins without the need for specific bioassays. The technique is similar to one previously described (Klein et al. (1996) Proc. Natl. Acad. Sci. USA 93, 7108-7113). We describe results using a cDNA library derived from activated human peripheral blood mononuclear cells (PBMC). Genes identified from this library encoded signal sequences of proteins of diverse structure, function, and cellular location such as cytokines, type 1 and type 2 transmembrane proteins, and proteins found in intracellular organelles. In addition, a number of novel secreted proteins were identified, including a chemokine and a novel G-protein-coupled receptor. Since signal sequences possess features conserved throughout evolution, the procedure can be used to isolate genes encoding secreted proteins from both eukaryotes and prokaryotes.

Amino Acid Sequence↗
PubMed1983

Aldosterone suppression with dopamine infusion in low-renin hypertension.

A dopaminergic mechanism has been proposed to suppress aldosterone secretion. To assess the possibility that a defect in the dopaminergic mechanism might enhance aldosterone secretion in hypertensive patients, we determined basal and adrenocorticotropic hormone (ACTH)-stimulated plasma aldosterone (PA), cortisol, renin activity, and potassium concentrations before and during dopamine receptor stimulation with dopamine infusion and bromocriptine administration and dopamine receptor blockade with metoclopramide. The patient study groups included: (a) seven patients with low-renin hypertension and abnormal aldosterone suppression with sodium loading and presumed bilateral zona glomerulosa hyperplasia (ZGHP); (b) two patients with aldosterone-producing adenoma; (c) five patients with low-renin hypertension but normal aldosterone suppression with sodium loading; and (d) six patients with normal-renin hypertension. Dopamine infusion in patients with ZGHP caused PA to fall (P less than 0.01) into the normal range, but did not block the enhanced (P less than 0.05) aldosterone response to ACTH that is characteristic of these patients. Dopamine infusion in patients with low-renin hypertension but normal aldosterone suppression also suppressed PA (P less than 0.01), whereas it had no effect upon PA in patients with normal-renin hypertension or aldosterone-producing adenoma and did not blunt the PA response to ACTH in either group. Bromocriptine administration had no effect upon basal or ACTH-stimulated PA. Dopamine infusion in patients with ZGHP also enhanced (P less than 0.05) diuresis and natriuresis in comparison with normal-renin patients. Metoclopramide administration increased (P less than 0.01) PA in all patients. Thus, a dopaminergic mechanism appears to be important in the regulation of aldosterone secretion in patients with ZGHP and in other low-renin hypertensives with normal aldosterone suppression with sodium loading. In contrast, this latter group does not exhibit an enhanced aldosterone response to ACTH. Both of these groups differ from normal-renin hypertensives, who have no PA suppression with dopamine infusion.

Adenoma↗
PubMed1976

Tumor hypoglycemia: deficient splanchnic glucose output and deficient glucagon secretion.

Fasting hypoglycemia occurred in a patient with a histologically benign mesothelioma; the serum insulin was low (2-4 muU./ml.), as was the glucose utilization rate. Splanchnic glucose output was markedly decreased on direct measurement (21 mg./min.; normal: 108-180 mg./min.). Splanchnic uptake of gluconeogenic substrates plasma glucagon was low normal during hypoglycemia and responded poorly to oral and intravenous alanine. The nonsuppressible insulin-like (NSILA-s) and somatomedin-like activities of the serum were not elevated, and the tumor did not release insulin-like activity on incubation nor did it contain somatostatin. The marked decrease in splanchnic glucose output was the principal cause of hypoglycemia, was associated with an apparent decrease in glycogenolysis, and was at least partly due to deficient glucagon secretion. The relationship of the tumor to these defects is unclear. The tumor may have secreted an unknown insulin-like material affecting primarily the liver and/or pancreatic alpha cell. The approach used here may serve as a paradigm for the analysis of hypoglycemia not caused by excessive insulin.

Glucagon↗
PubMed2001

Foxa3 (hepatocyte nuclear factor 3gamma ) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast.

The winged helix transcription factors, hepatocyte nuclear factors 3alpha, -beta, and -gamma (HNF-3, encoded by the Foxa1, -a2, and -a3 genes, respectively), are expressed early in embryonic endoderm and play important roles in the regulation of gene expression in liver and pancreas. Foxa1 has been shown to be required for glucagon secretion in the pancreas, whereas Foxa2 is critical for the regulation of insulin secretion in pancreatic beta-cells. Here we address the role of Foxa3 in the maintenance of glucose homeostasis. Mice homozygous for a null mutation in Foxa3 appear normal under fed conditions. However, when fasted, Foxa3(-/-) mice have a significantly lower blood glucose compared with control mice. The fasting hypoglycemia in Foxa3(-/-) mice could not be attributed to defects in pancreatic hormone secretion, ketone production, or hepatic glycogen breakdown. Surprisingly, mRNA levels for several gluconeogenic enzymes were up-regulated appropriately in fasted Foxa3(-/-) mice, despite the fact that the corresponding genes had been shown to be activated by FOXA proteins in vitro. However, the mRNA for the plasma membrane glucose transporter GLUT2 was decreased by 64% in the fasted and 93% in the fed state, suggesting that efflux of newly synthesized glucose is limiting in Foxa3(-/-) hepatocytes. Thus, Foxa3 is the dominating transcriptional regulator of GLUT2 expression in hepatocytes in vivo. In addition, we investigated the hepatic transcription factor network in Foxa3(-/-) mice and found that the normal activation of HNF-4alpha, HNF-1alpha, and PGC-1 induced by fasting is attenuated in mice lacking Foxa3.

Animals↗
PubMed1989

Human immunodeficiency virus infection of helper T cell clones. Early proliferative defects despite intact antigen-specific recognition and interleukin 4 secretion.

HIV selectively inhibited the proliferative response of clonal CD4+ T lymphocytes to alloantigen while other alloantigen-dependent responses were unperturbed. Specifically, impaired blastogenesis could be dissociated from alloantigen-specific induction of the B cell activation molecule CD23, IL-4 release, and inositol lipid hydrolysis. In addition, membrane expression of pertinent T cell receptor molecules, including CD2, CD3, and T cell antigen receptor (Ti), remained intact. Using two MHC class II-specific human CD4+ helper T cell clones, the proliferative defect was shown to be an early consequence of HIV infection, occurring within 4 d of viral inoculation and preceding increases in mature virion production. It was generalizable to three distinct methods of T cell activation, all independent of antigen-presenting cells: anti-CD3 mediated cross-linking of the CD3/Ti complex; anti-CD2 and phorbol 12-myristic 13-acetate (PMA); and anti-CD28 plus PMA. These abnormalities were not mitigated by addition of exogenous IL-2, even though expression of the IL-2 receptor (CD25) was unaltered. These studies define a selective blockade in T cell function early after HIV exposure that could serve as a model for certain in vivo manifestations of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Assessment of insulin resistance in vivo: application to the study of type 2 diabetes.

Besides insulin secretion, insulin sensitivity plays a key role in the feedback glucose-insulin closed loop. It can be altered in numerous physiological, pathological and pharmacological conditions. It can be estimated in vivo using methods that open the feedback loop (insulin suppression test, glucose clamp) or that analyze the closed loop by employing mathematical models of glucose kinetics. The most popular method is the euglycemic hyperinsulinemic glucose clamp. This test should be ideally coupled with a priming-constant infusion of a glucose tracer together with indirect calorimetry. This combination allows to study the glucose kinetics (Ra and Rd, and thus endogenous-mainly hepatic-glucose production) and its metabolism (oxidation or storage as glycogen), respectively. One alternative approach is the frequently sampled intravenous glucose tolerance test where the dynamic changes in plasma insulin and glucose levels are analyzed using the so-called 'minimal model' method. Noninsulin-dependent or type 2 diabetes is characterized by a significant defect in both insulin secretion and action. The insulin resistance is located at the liver site (increased glucose production) and at the peripheral tissues (decreased oxidation and, even more, defective storage of glucose in the muscles). This insulin resistance, which predominates at the postreceptor level, seems to be genetically determined but is worsened by weight excess and by hyperglycemia itself. This contributes to a vicious circle which aggravates progressively the severity of the disease.

Blood Glucose↗
PubMed2005

The Legionella pneumophila tatB gene facilitates secretion of phospholipase C, growth under iron-limiting conditions, and intracellular infection.

Our previous mutational analysis of Legionella pneumophila demonstrated a role for type II protein (Lsp) secretion and iron acquisition in intracellular infection and virulence. In gram-negative bacteria, the twin-arginine translocation (Tat) pathway is involved in secretion of proteins, including components of respiratory complexes, across the inner membrane to the periplasm. To assess the significance of Tat for L. pneumophila, tatB mutants were characterized. The mutants exhibited normal growth in standard media but grew slowly under low-iron conditions. They were also impaired in the Nadi assay, indicating that the function of cytochrome c oxidase is influenced by tatB. Consistent with this observation, a subunit of the cytochrome c reductase was shown to be a Tat substrate. Supernatants of the tatB mutants showed a 30% reduction in phospholipase C activity while maintaining normal levels of other Lsp secreted activities. When tested for infection of U937 macrophages, the tatB mutants showed a 10-fold reduction in growth. Double mutants lacking tatB and Lsp secretion were even more defective, suggesting tatB has an intracellular role that is independent of Lsp. tatB mutants were also impaired 20-fold in Hartmannella vermiformis amoebae cultured in the presence of an iron chelator. All mutant phenotypes were complemented by reintroduction of an intact tatB. Thus, L. pneumophila tatB plays a role in the formation of a respiratory complex, growth under low-iron conditions, the secretion of a phospholipase C activity, and intracellular infection.

Amino Acid Sequence↗
PubMed1988

Abnormal regulation of cAMP accumulation in pancreatic islets of obese mice.

The present study was undertaken 1) to determine whether a defect in the regulation of adenosine 3',5'-cyclic monophosphate (cAMP) accumulation was present in the beta-cell of the ob/ob mouse, 2) to determine how such a defect, if present, would alter the regulation of insulin secretion in these islets, and 3) to find out if epinephrine had similar effects on insulin secretion and cAMP production in islets of lean and obese mice. In the obese mouse, inhibitory modulators neither inhibited cAMP accumulation in intact islets nor adenylate cyclase activity in islet homogenates. These anomalies in the modulation of cAMP accumulation were not correlated with a failure to inhibit insulin secretion. It is concluded that, first, a defect in cAMP modulation is present in the islets of Langerhans of the obese mouse; second, epinephrine produces its effects on insulin secretion and cAMP accumulation via distinct mediators; and third, an anomaly in the adenylate cyclase system is unlikely to be the cause of the exaggerated insulin secretion in the islet of the ob/ob mouse. It is more likely that the exaggerated insulin secretion is due to a faulty cation gating mechanism that, in turn, may contribute to the impaired ability of the islet to accumulate cAMP.

Adenylate Cyclase Toxin↗
PubMed2003

Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-dependent airway epithelial bicarbonate transport is hypothesized to participate in airway surface liquid pH regulation and contribute to lung defense. We measured pH and ionic composition in apical surface liquid (ASL) on polarized normal (NL) and CF primary bronchial epithelial cell cultures under basal conditions, after cAMP stimulation, and after challenge with luminal acid loads. Under basal conditions, CF epithelia acidified ASL more rapidly than NL epithelia. Two ASL pH regulatory paths that contributed to basal pH were identified in the apical membrane of airway epithelia, and their activities were measured. We detected a ouabain-sensitive (nongastric) H+,K+-ATPase that acidified ASL, but its activity was not different in NL and CF cultures. We also detected the following evidence for a CFTR-dependent HCO3- secretory pathway that was defective in CF: (i). ASL [HCO3-] was higher in NL than CF ASL; (ii). activating CFTR with forskolin/3-isobutyl-1-methylxanthine alkalinized NL ASL but acidified CF ASL; and (iii). NL airway epithelia more rapidly and effectively alkalinized ASL in response to a luminal acid challenge than CF epithelia. We conclude that cultured human CF bronchial epithelial pHASL is abnormally regulated under basal conditions because of absent CFTR-dependent HCO3- secretion and that this defect can lead to an impaired capacity to respond to airway conditions associated with acidification of ASL.

Bicarbonates↗
PubMed2006

Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system.

Excessive secretion of glucagon is a major contributor to the development of diabetic hyperglycemia. Secretion of glucagon is regulated by various nutrients, with glucose being a primary determinant of the rate of alpha cell glucagon secretion. The intra-islet action of insulin is essential to exert the effect of glucose on the alpha cells since, in the absence of insulin, glucose is not able to suppress glucagon release in vivo. However, the precise mechanism by which insulin suppresses glucagon secretion from alpha cells is unknown. In this study, we show that insulin induces activation of GABAA receptors in the alpha cells by receptor translocation via an Akt kinase-dependent pathway. This leads to membrane hyperpolarization in the alpha cells and, ultimately, suppression of glucagon secretion. We propose that defects in this pathway(s) contribute to diabetic hyperglycemia.

Animals↗
PubMed1986

Evidence for normal in vitro Ca2+-stimulated insulin release in rats with non-insulin-dependent diabetes.

Non-insulin-dependent diabetes (NIDD) was induced in adult rats following a neonatal injection of streptozotocin. Rats with NIDD exhibited moderate basal hyperglycemia (less than 2g/l) with defective glucose-induced insulin secretion and preserved or enhanced responsiveness to various non-glucose secretagogues. The possible sites of defects in the B cells of these diabetic rats are at present unknown. Extracellular Ca2+ at concentrations exceeding 10 mmol/l causes a dose-related stimulation of insulin release by the perfused normal rat pancreas. This technique provokes an increase of cytosolic Ca2+ accumulation in the B cell sufficient to trigger activation of the microtubular-microfilamentous effector system responsible for the exocytosis of insulin granules. It is therefore possible to compare functional efficiency of this process in the B cells of diabetic rats to that in the normal B cells. Results obtained in response to Ca2+ stimulation over the range 10-13.5 mmol/l provide evidence that the insulin release is stimulated in the pancreas of diabetic rats to the same extent as that in the controls, in both the kinetic and the quantitative aspect of the response. These data are compatible with the idea that in the B cells of rats with NIDD : 1) the effector system of insulin secretion is not grossly altered and 2) the lesion responsible for the loss of glucose-induced insulin secretion occurs before the effector system, involving either the mechanism by which glucose is metabolized as previously proposed by us, or another step yet to be identified.

Animals↗
PubMed2004

A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion.

Mutations in ATP8B1, a broadly expressed P-type ATPase, result, through unknown mechanisms, in disorders of bile secretion. These disorders vary in severity from mild and episodic to progressive with liver failure. We generated Atp8b1G308V/G308V mutant mice, which carry a mutation orthologous to that present in homozygous form in patients from the Amish index kindred for severe ATP8B1 disease. In contrast to human patients, Atp8b1(G308V/G308V) mice had unimpaired bile secretion and no liver damage, but showed mild abnormalities including depressed weight at weaning and elevated serum bile salt levels. We challenged the hepatobiliary metabolism of Atp8b1G308V/G308V mice by administering exogenous bile salts. Upon bile salt feeding, Atp8b1G308V/G308V mice, but not wild-types, demonstrated serum bile salt accumulation, hepatic injury and expansion of the systemic bile salt pool. Unexpectedly, this failure of bile salt homeostasis occurred in the absence of any defect in hepatic bile secretion. Upon infusion of a hydrophobic bile salt, wild-type mice developed cholestasis while Atp8b1G308V/G308V mice maintained high biliary output and more extensively rehydroxylated the infused bile salt. Increased bile salt hydroxylation, which reduces bile salt toxicity, may explain the milder phenotype in Atp8b1G308V/G308V mice compared with humans with the equivalent mutation. These results demonstrate the key role of Atp8b1 in bile salt homeostasis and highlight the importance of bile salt hydroxylation in the prevention of cholestasis. The mouse phenotype reveals that loss of Atp8b1 disrupts bile salt homeostasis without impairment of canalicular bile secretion; in humans this process is likely to be obscured by early onset of severe liver disease.

Adenosine Triphosphatases↗
PubMed2003

Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features.

Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into two discrete halves. Gli2 is one of three vertebrate transcription factors implicated as obligatory mediators of Shh signal transduction. Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia. We also demonstrate that these mutations lack GLI2 activity. We report on a functional association between GLI2 and human disease and highlight the role of GLI2 in human head development.

Alleles↗
PubMed2004

SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1.

XLP is caused by mutations affecting SAP, an adaptor that recruits Fyn to SLAM family receptors. SAP-deficient mice recapitulate features of XLP, including increased T cell activation and decreased humoral responses post-infection. SAP-deficient T cells also show increased TCR-induced IFN-gamma and decreased T(H)2 cytokine production. We demonstrate that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-gamma production. SAP-deficient cells respond normally to polarizing cytokines, yet show impaired TCR-mediated induction of GATA-3 and IL-4. Examination of TCR signaling revealed normal Ca(2+) mobilization and ERK activation in SAP-deficient cells, but decreased PKC-theta recruitment, Bcl-10 phosphorylation, IkappaB-alpha degradation, and nuclear NF-kappaB1/p50 levels. Similar defects were observed in Fyn-deficient cells. SLAM engagement amplified PKC-theta recruitment in wt but not SAP- or Fyn-deficient cells, arguing that a SAP/Fyn-mediated pathway enhances PKC-theta/NF-kappaB1 activation and suggesting a role for this pathway in T(H)2 regulation.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The defects in effector generation associated with aging can be reversed by addition of IL-2 but not other related gamma(c)-receptor binding cytokines.

Aged naive CD4 T cells produce low levels of IL-2, leading to inefficient generation of effectors. The cells expand poorly, giving rise to few effectors with less activated phenotypes and reduced ability to produce cytokines. The aged cells also respond less vigorously in vivo. Addition of exogenous IL-2 or other gamma(c) receptor-signaling cytokines, restores expansion. However, only effectors generated in the presence of IL-2, are able to produce IL-2 in normal amounts and to become polarized to secrete Th2 cytokines. The defect in IL-2 production may be the only critical deficiency of aged naive CD4 T cells. Importantly, memory CD4 T cells generated from the IL-2 "restored" effectors are also deficient in IL-2 production, suggesting that a heritable change occurs during aging which effects production of IL-2 by resting naive and memory CD4 T cells, but not by optimally generated effectors.

Aging↗
PubMed1999

Disruption of circadian insulin secretion is associated with reduced glucose uptake in first-degree relatives of patients with type 2 diabetes.

The objective of this study was to evaluate whether first-degree relatives (FDRs) of patients with type 2 diabetes had abnormal circadian insulin secretion and, if so, whether this abnormality affected their glucose metabolism. Six African-American FDRs with normal glucose tolerance and 12 matched normal control subjects (who had no family history of diabetes) were exposed to 48 h of hyperglycemic clamping (approximately 12 mmol/l). Insulin secretion rates (ISRs) were determined by deconvolution of plasma C-peptide levels using individual C-peptide kinetic parameters. Detrending and smoothing of data (z-scores) and computation of autocorrelation functions were used to identify ISR cycles. During the initial hours after start of glucose infusions, ISRs were approximately 60% higher in FDRs than in control subjects (585 vs. 366 nmol/16 h, P < 0.05), while rates of glucose uptake were the same (5.6 mmol x kg(-1) x h(-1)), indicating that the FDRs were insulin resistant. Control subjects had well-defined circadian (24 h) cycles of ISR and plasma insulin that rose in the early morning, peaked in the afternoon, and declined during the night. In contrast, FDRs had several shorter ISR cycles of smaller amplitude that lacked true periodicity. This suggested that the lack of a normal circadian ISR increase had made it impossible for the FDRs to maintain their compensatory insulin hypersecretion beyond 18 h of hyperglycemia. As a result, ISR decreased to the level found in control subjects, and glucose uptake fell below the level of control subjects (61 vs. 117 micromol x kg(-1) x min(-1), P < 0.05). In summary, we found that FDRs with normal glucose tolerance had defects in insulin action and secretion. The newly recognized insulin secretory defect consisted of disruption of the normal circadian ISR cycle, which resulted in reduced insulin secretion (and glucose uptake) during the ascending part of the 24 h ISR cycle.

Adult↗
PubMed2002

Effect of high dietary fat on insulin secretion in genetically diabetic Goto-Kakizaki rats.

INTRODUCTION AND AIM: To clarify the effects of a high fat-diet on insulin secretion from genetically diabetic beta cells, Goto-Kakizaki rats and Wistar rats were subjected to oral glucose tolerance test (OGTT) after 12-week high-fat feeding. METHODOLOGY: We compared Wistar and Goto-Kakizaki (GK) rats fed a high-fat diet (45% fat content) for 12 weeks, measuring insulin secretion and insulin release. RESULTS: Insulin secretion during oral glucose tolerance test (OGTT) was enhanced in high-fat diet-fed Wistar rats (WF) with normal glucose tolerance. Insulin secretion in high-fat diet-fed GK rats (GF) during OGTT also was enhanced together with deteriorated glucose tolerance. Basal insulin release from the isolated perfused pancreas at 3.3 m glucose in WF was comparable to that in normal chow-fed Wistar rats (WN), but basal insulin release in GF was remarkably higher than in normal chow-fed GK rats (GN). Stimulated insulin release induced by 16.7 m glucose was remarkably increased in WF compared with WN. Total insulin release at 16.7 m glucose in both GK rat groups was similar and minimal. CONCLUSION: These results indicate that normal pancreatic beta-cells have the ability to secrete sufficient insulin to compensate for the insulin resistance induced by a high-fat diet. In contrast, glucose metabolism in diabetic rats after high-fat diet deteriorated partly because of insufficient insulin secretion caused by genetic defects and lipotoxicity due to chronically high FFA levels.

Animals↗
PubMed1999

Evolution of beta-cell dysfunction in impaired glucose tolerance and diabetes.

Patients with overt Type 2 diabetes consistently have alterations in insulin secretion, including reduced insulin secretory responses to glucose, delayed and blunted meal-induced insulin secretion, increased pro-insulin and abnormal insulin secretory oscillations. More recently, it has become evident that abnormal insulin secretion antedates the onset of overt hyperglycaemia and is present in people with impaired glucose tolerance, i.e. normal fasting glucose and glycohaemoglobin concentrations. These defects are subtle and include shifts to the right in the dose-response curves that relate to glucose and insulin secretion, reduced ability of the beta-cell to detect and respond to oscillatory changes in the plasma glucose concentration and impaired beta-cell compensation for insulin resistance. In order to define the factors responsible for these defects in secretion, we have infused human patients with a lipid emulsion and heparin to raise plasma free fatty acid concentrations. This is associated with reduced ability of the beta-cell to detect and respond to small changes in the plasma glucose concentration. In summary, defects in insulin secretion are consistently present in patients with impaired glucose tolerance and play a critical role in the progression from impaired glucose tolerance to diabetes.

Diabetes Mellitus, Type 2↗